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Criteria, and Characteristics of Extramural Grants Made with Recovery 
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Report to Congressional Requesters: 

United States Government Accountability Office: 
GAO: 

August 2010: 

National Institutes of Health: 

Awarding Process, Awarding Criteria, and Characteristics of Extramural 
Grants Made with Recovery Act Funding: 

GAO-10-848: 

GAO Highlights: 

Highlights of GAO-10-848, a report to congressional requesters. 

Why GAO Did This Study: 

The American Recovery and Reinvestment Act of 2009 (Recovery Act) 
included $10.4 billion in funding for the National Institutes of 
Health (NIH), an agency of the Department of Health and Human Services 
(HHS). Of the NIH Recovery Act funding, $8.2 billion was to be used to 
support additional scientific research and $400 million for 
comparative effectiveness research, including extramural research at 
universities and research institutions. NIH is comprised of the Office 
of the Director (OD) and 27 Institutes and Centers (IC), 24 of which 
make grant funding decisions. 

GAO was asked to report on how NIH awarded Recovery Act funds for 
scientific research and the information that NIH made available about 
the award of these funds. This report describes the (1) process and 
criteria NIH used to award extramural grants using Recovery Act 
funding, and (2) characteristics of Recovery Act extramural grants and 
the information made publicly available about these grants. GAO 
interviewed NIH officials in the OD and the three ICs that received 
the largest proportion of Recovery Act funds, and reviewed related 
documents, such as NIH guidance on awarding grants using Recovery Act 
funds. GAO also obtained and analyzed NIH data on all Recovery Act 
grants awarded as of April 2010. Appendix I of this report contains 
information provided by NIH about 45 randomly selected 
nonrepresentative Recovery Act extramural grants, ranging from about 
$13,000 to about $7.2 million. 

What GAO Found: 

NIH used its standard review processes—peer review, which comprises 
two sequential levels of review by panels of experts in various fields 
of research, or administrative review—to award extramural grants using 
Recovery Act funds. These standard review processes were used for 
three categories of extramural grant applications: (1) new grant 
applications from Recovery Act funding announcements; (2) existing 
grant applications that had not previously received NIH funding; and 
(3) administrative supplements and competitive revisions to current 
active grants. For new grant applications submitted in response to 
Recovery Act funding announcements, NIH followed its standard peer 
review process. For existing grant applications, which had already 
undergone the peer review process, each of the three ICs GAO reviewed—
National Cancer Institute (NCI), National Institute of Allergy and 
Infectious Diseases (NIAID), and National Heart, Lung, and Blood 
Institute (NHLBI)—selected additional applications for Recovery Act 
funding based in part on the amount of this funding available to each 
IC. To award administrative supplements, NIH conducted its standard 
administrative review at the IC level, and for competitive revisions 
NIH followed its standard peer review process. In reviewing 
applications, NIH used its standard criteria—scientific merit, 
availability of funds, and relevance to scientific priorities—plus 
three criteria for Recovery Act grants. These criteria were the 
geographic distribution of Recovery Act funds, the potential for job 
creation, and the potential for making scientific progress within a 2-
year period. 

NIH's Recovery Act grant awards varied across three grant categories 
and other characteristics, and NIH made a variety of information about 
the grants publicly available. NIH data show that as of April 2010, 
about $7 billion of the $8.6 billion in Recovery Act scientific 
research and comparative effectiveness research funds had been awarded 
for 14,152 extramural grants. NIH awarded nearly $2.7 billion to make 
extramural grants for existing grant applications that had not 
previously received funding, slightly over $2.4 billion for new grant 
applications, and about $1.9 billion for administrative supplements 
and competitive revisions. NIH officials reported that the remaining 
Recovery Act scientific research funds will be awarded by the end of 
fiscal year 2010. At the three ICs GAO reviewed, the distribution of 
Recovery Act funds to the three categories of Recovery Act extramural 
grants varied significantly. For example, GAO found that as of April 
2010, NIAID used 69 percent of its Recovery Act funds for existing 
grant applications that had not previously received NIH funding, while 
NCI used 31 percent for these existing grant applications. The average 
NIH Recovery Act extramural grant award was about half a million 
dollars, and about 25 percent of grantees were awarded $623,000 or 
more. Through NIH’s Web sites, NIH and the ICs communicated a variety 
of information to the public about Recovery Act extramural grant 
awards, such as information about grantees and awarding ICs. 

HHS provided technical comments on a draft of this report, which GAO 
incorporated as appropriate. 

View [hyperlink, http://www.gao.gov/products/GAO-10-848] or key 
components. For more information, contact Linda T. Kohn at (202) 512-
7114 or kohnl@gao.gov. 

[End of section] 

Contents: 

Letter: 

Background: 

NIH Used Standard Review Processes and Applied Standard and Recovery 
Act-Specific Criteria to Make Extramural Grant Awards with Recovery 
Act Funding: 

NIH's Recovery Act Grant Awards Varied across Grant Categories and 
Other Characteristics, and NIH Made Information about the Grants and 
Grantees Publicly Available: 

Agency Comments: 

Appendix I: Illustrative Examples of NIH Recovery Act Extramural 
Grants: 

Appendix II: GAO Contact and Staff Acknowledgments: 

Figure: 

Figure 1: Selected ICs' Recovery Act Extramural Grant Awards, as of 
April 2010: 

Abbreviations: 

CER:comparative effectiveness research: 

GO:Grand Opportunity: 

HHS:Department of Health and Human Services: 

IC: Institutes and Centers: 

IDeA: Institutional Development Award: 

NCI: National Cancer Institute: 

NHLBI: National Heart, Lung, and Blood Institute: 

NIAID: National Institute of Allergy and Infectious Diseases: 

NIH: National Institutes of Health: 

OD: Office of the Director: 

Recovery Act: American Recovery and Reinvestment Act of 2009: 

RePORT: Research Portfolio Online Reporting Tools: 

[End of section] 

United States Government Accountability Office:
Washington, DC 20548: 

August 6, 2010: 

The Honorable Mitch McConnell: 
Republican Leader: 
United States Senate: 

The Honorable Joe Barton: 
Ranking Member: 
Committee on Energy and Commerce: 
House of Representatives: 

Among its many provisions, the American Recovery and Reinvestment Act 
of 2009 (Recovery Act)[Footnote 1] provided funding for investments in 
science and health at the National Institutes of Health (NIH), an 
agency of the Department of Health and Human Services (HHS) that is 
the primary federal agency for supporting medical research in the 
United States. The Recovery Act designated a total of $10.4 billion 
for NIH, with $8.2 billion of that amount to be used to support 
additional scientific research, including extramural grants, which 
support scientific research at universities, medical schools, and 
other research institutions. Included in the $10.4 billion was $400 
million to be used to fund comparative effectiveness research (CER). 
[Footnote 2] 

NIH comprises 27 Institutes and Centers (IC) and an Office of the 
Director (OD). Twenty-four of the 27 ICs fund extramural research, and 
these ICs have their own budget, mission, and staff and focus on 
particular diseases or research areas, such as cancer or aging issues. 
Through its ICs, NIH funds extramural research each year using annual--
non-Recovery Act--appropriations.[Footnote 3] For fiscal year 2009, 
NIH awarded about $24 billion in extramural funding from its annual 
appropriations. In awarding these funds, NIH follows a process of peer 
review--by panels of experts--required by law and NIH policy and 
generally bases its decisions on criteria such as scientific merit, 
relevance to the IC's scientific priorities, and availability of funds. 

The Recovery Act included an appropriation to the OD to support NIH's 
scientific research, but provided that most of the funding be 
transferred to the ICs in proportion to the appropriation each IC 
received for fiscal year 2009.[Footnote 4] NIH is required to use its 
Recovery Act funding within a 2-year window--specifically, in fiscal 
years 2009 and 2010.[Footnote 5] Within these limitations, NIH has 
discretion regarding how to use the funding and what grants to award 
with it. 

Congress included numerous transparency provisions in the Recovery 
Act, so that the public can see how its money is being spent and what 
is being achieved. You requested that we report on how NIH awarded its 
Recovery Act funds and identify information that NIH has made publicly 
available about these awards. This report describes (1) the process 
and criteria NIH used in fiscal years 2009 and 2010 to award 
extramural scientific research grants with funding made available by 
the Recovery Act and (2) the characteristics of the extramural 
scientific research grants NIH awarded using the Recovery Act funding 
and the information NIH has made publicly available about these 
extramural grants. 

To identify the process and criteria NIH used for awarding extramural 
scientific research grants[Footnote 6] through funding made available 
under the Recovery Act, we reviewed the Recovery Act for criteria on 
awarding Recovery Act funds. We also reviewed guidance and other 
relevant documents identified by NIH officials, as well as guidance 
and other policies posted on NIH's internal and Internet Web sites. We 
reviewed the specific process and criteria used at three ICs--National 
Cancer Institute (NCI), National Institute of Allergy and Infectious 
Diseases (NIAID), and National Heart, Lung, and Blood Institute 
(NHLBI). These ICs were selected because they received the largest 
proportions of Recovery Act funding designated to support scientific 
research, not including repairs, improvements, and construction, as 
well as scientific equipment.[Footnote 7] We also interviewed NIH 
officials with the OD, NIH's Office of General Counsel, and the three 
selected ICs about Recovery Act grant award processes and criteria. 

To provide information on the characteristics of the extramural 
research grants funded by the ICs for fiscal years 2009 and 2010 using 
Recovery Act funding, we obtained from NIH data on all grants that 
have been awarded using Recovery Act funds as of April 2010. The data 
covered grants awarded by each of the ICs that received Recovery Act 
funds and the OD.[Footnote 8] The data included grant characteristics 
such as the awarding IC, the grant award size (in dollars), and the 
institution receiving the grant.[Footnote 9] We analyzed the data to 
determine, among other things, the amount of Recovery Act extramural 
research funds awarded by each of the ICs and the geographic location 
of grantees, as well as the average dollar amount of extramural grant 
awards (including the amount of funds NIH has committed to grantees), 
and the number of extramural grants awarded. In cases where Recovery 
Act funds appropriated to and retained in the OD were used for 
extramural grants that were administered by an IC, we classified the 
grant and associated funding under the administering IC. To provide 
more information about the extramural grants awarded through the 
Recovery Act, we selected a sample of 15 extramural grants awarded 
with Recovery Act funds from each of the three ICs we reviewed (for a 
total of 45 grants). These 15 grants were randomly selected from the 
different categories of grant applications received by the ICs. The 
number of grants selected in each grant category was in proportion to 
the amount of Recovery Act funding awarded for each category by the 
IC, and are not representative of all Recovery Act extramural grant 
awards. Appendix I of this report includes specific details about 
these 45 extramural grants. To determine what information NIH made 
publicly available[Footnote 10] about the extramural grants funded 
through the Recovery Act, we reviewed NIH's Web site and the Web sites 
of the three ICs for Recovery Act grant award information. We also 
interviewed NIH officials to identify the information about Recovery 
Act grant awards made publicly available by NIH and reviewed related 
documents. 

To ensure that the data provided by NIH were sufficiently reliable for 
our analyses, we obtained information from agency officials 
knowledgeable about NIH extramural grant award data. We also performed 
data quality checks to assess the reliability of the Recovery Act 
extramural grants data file received from NIH. These data quality 
checks involved an assessment to identify incorrect and erroneous 
entries or outliers.[Footnote 11] Based on the information we obtained 
and analyses we conducted, we determined that the data were 
sufficiently reliable for the purposes of this report. We conducted 
this performance audit from December 2009 to August 2010, in 
accordance with generally accepted government auditing standards. 
Those standards require that we plan and perform the audit to obtain 
sufficient, appropriate evidence to provide a reasonable basis for our 
findings and conclusions based on our audit objectives. We believe 
that the evidence obtained provides a reasonable basis for our 
findings and conclusions based on our audit objectives. 

Background: 

NIH's extramural research funding efforts reflect its large, 
decentralized organization.[Footnote 12] Twenty-four of the 27 ICs 
fund extramural research, each with a separate appropriation,[Footnote 
13] and these ICs make final decisions on which extramural research 
projects to fund following a standard peer review process defined by 
law and NIH policy. As the central office at NIH, the OD establishes 
NIH policy and is responsible for overseeing the ICs, including their 
extramural research funding efforts, to ensure that ICs operate in 
accordance with NIH's policies. 

NIH's Standard Process and Criteria for Awarding Extramural Grants: 

NIH is required by law to use a peer review system in its process for 
making extramural grant awards.[Footnote 14] In September 2009 we 
described this peer review system[Footnote 15] as two sequential 
levels of peer review by panels of experts in various fields of 
research that help NIH identify the most promising extramural grant 
applications to fund, as defined primarily by an assessment of the 
applications' scientific merit.[Footnote 16] 

Initial peer review groups conduct NIH's first level of peer review. 
These groups review the applications assigned to them and assess their 
scientific merit, using criteria that require reviewers to examine 
such components as a grant application's design and methodology, 
innovation, and scientific significance.[Footnote 17] Using these 
criteria, the initial peer review groups assign a priority 
score[Footnote 18] to the applications they review, which are used to 
rank the applications from among those in the cohort of applications. 
After the applications are scored and ranked, the information is 
forwarded to the appropriate IC--based on the applications' proposed 
area of research--for the second level of peer review. 

Each IC that funds extramural research has its own advisory council, 
[Footnote 19] which conducts the second level of NIH's peer review. 
[Footnote 20] Advisory councils consist of no more than 18 voting 
members, two-thirds of whom are scientists in the research areas of 
the IC and one-third of whom are leaders of nonscience fields. 
[Footnote 21] Under law and NIH policy, the advisory councils are 
responsible for reviewing the applications and their priority scores 
and, based on this review, recommending or not recommending to the ICs 
certain applications for funding consideration.[Footnote 22] The 
advisory councils' recommendations conclude NIH's peer review process. 

After NIH's peer review process has been concluded, the director of 
each IC is responsible for considering the recommendations of the 
advisory council and for making final extramural funding decisions. 
[Footnote 23] In general, NIH makes extramural grant award decisions 
based on scientific merit, relevance to the IC's scientific 
priorities, and the availability of funds appropriated to each IC. As 
noted previously, the scientific merit of extramural grant 
applications is determined by NIH's peer review system and reflected 
in the applications' priority scores. Each of the ICs focuses on 
specific scientific priorities. To aid in grant funding decisions, 
each IC establishes a funding line--known as the payline--which is 
determined by the number of extramural grant applications the IC 
anticipates funding that year. The payline for any given year is based 
on projections of the total funding available at the IC that year for 
grants, the average dollar amount expected to be awarded per 
application, and the number of applications received by the IC. While 
IC directors typically fund applications that fall within the payline, 
they are not required to fund applications based strictly on the 
applications' priority scores or the payline. 

After the ICs determine which extramural grant applications to fund, 
they must also determine the specific award amount and the length of 
the grant project. Determining the specific award amount may involve 
negotiation between NIH and the grant applicant, as well as the 
submission of additional documentation by the grant applicant prior to 
awarding the grant. For example, NIH may ask an applicant to reduce 
the scope and the proposed budget for the grant application if the IC 
does not have sufficient funds to provide 100 percent of the funding 
requested by the grant applicant. NIH grants may be funded for up to a 
5-year project period, with funding for each year contingent on the 
availability of funds and satisfactory progress of the project. 

Administrative Supplements and Competitive Revisions to Existing 
Extramural Grants: 

NIH's ICs may provide additional funding to current active grants 
through both administrative supplements and competitive revisions. The 
ICs award administrative supplements using an administrative review 
process at the IC level. Administrative supplements award additional 
funds during the current project period to an existing extramural 
grant award that was previously peer reviewed--for example, by 
allowing grantees to add personnel or purchase additional equipment. 
All additional costs must be within the scope of the peer reviewed and 
approved project. Competitive revisions are funds added to existing 
extramural grant awards in order to support new research objectives or 
other changes in scope. Like the original grant award to which they 
are added, competitive revisions are awarded using NIH's peer review 
process. 

Historical Funding of NIH non-Recovery Act Extramural Grant 
Applications: 

In fiscal year 2009, NIH received over 26,000 non-Recovery Act grant 
applications for R01-equivalent grants--R01 grants are the most common 
type of extramural grant applications--and 22 percent of these 
applications were funded for an average of $391,000. NIH awards grants 
in all 50 states, Washington, D.C., and other territories and 
possessions of the United States, and to foreign institutions and 
international organizations. In fiscal year 2009 NIH awarded about two-
thirds of all non-Recovery Act grant funds, including extramural 
research grant funds, to institutions in 10 states: California, 
Illinois, Maryland, Massachusetts, New York, North Carolina, Ohio, 
Pennsylvania, Texas, and Washington. 

NIH Used Standard Review Processes and Applied Standard and Recovery 
Act-Specific Criteria to Make Extramural Grant Awards with Recovery 
Act Funding: 

NIH used its standard review processes--peer review or administrative 
review--to make extramural grant awards with its Recovery Act funding. 
NIH selected grant applications for Recovery Act funding based on NIH 
standard review criteria, as well as three criteria for Recovery Act 
grants. 

NIH Used Its Standard Review Processes, Including Peer Review, to 
Award Extramural Research Grants Using Recovery Act Funding: 

In order to make extramural grant awards in fiscal years 2009 and 
2010, NIH used its standard review processes. These standard processes 
were used to review three categories of applications for Recovery Act-
funded extramural grants, namely (1) new grant applications received 
from Recovery Act funding announcements;[Footnote 24] (2) existing 
grant applications that NIH received prior to the Recovery Act, but 
did not fund; and (3) applications for administrative supplements and 
competitive revisions to current active grants. Specifically, 

* NIH followed its standard peer review process, including review by 
an initial peer review group and an IC advisory council, to evaluate 
new grant applications submitted in response to Recovery Act-specific 
funding opportunity announcements.[Footnote 25] Specifically, 
Challenge and Grand Opportunity (GO) grants were developed for 
Recovery Act funding.[Footnote 26] 

* For existing grant applications that had not previously received NIH 
funding, the three ICs we reviewed set a new payline to guide 
selection of existing grant applications for Recovery Act funding. 
[Footnote 27] These applications had been submitted for NIH funding 
from annual appropriations prior to the Recovery Act, and had already 
been reviewed and determined to be scientifically meritorious using 
NIH's peer review process. According to NIH officials, most grant 
applications that fell within the new payline set by the ICs were 
selected for renegotiation to reduce the projects' proposed 
objectives, scope, and budget. These renegotiations were required 
because most grant applications were originally submitted for more 
than 2 years of funding while NIH generally limited grants under the 
Recovery Act to projects requiring 2 years or less to complete. NIH 
and IC officials reported that grant management and program staff 
ensured that grant applications remained scientifically meritorious 
when they rescoped 4-year grant applications down to 2 years, but did 
not assign new priority scores to them. 

* NIH also followed its standard review processes in awarding 
administrative supplements and competitive revisions to current active 
grants. For applications for administrative supplements to current 
active grants, ICs conducted an administrative review of the 
supplemental request for grant funding. Administrative supplements 
provide additional funding to existing extramural grant awards that 
were previously peer reviewed. For competitive revisions to current 
active grants, ICs conducted a standard peer review of the new grant 
application. 

NIH Awarded Recovery Act Funds Based on Standard NIH Criteria, Such as 
Scientific Merit and Relevance to IC Scientific Priorities, as Well as 
Criteria for Recovery Act Grants: 

NIH based funding decisions for all Recovery Act extramural grant 
awards in fiscal years 2009 and 2010 on the three standard criteria 
NIH uses to award extramural grants, plus three additional criteria 
established by NIH. The three standard NIH criteria are scientific 
merit, availability of funds, and relevance to IC scientific 
priorities: 

* Scientific merit--NIH considered the design and methodology, 
innovation, and scientific significance of each grant application 
using the scientific merit priority scores assigned to new grant 
applications, existing grant applications that had not previously 
received NIH funding, and competitive revisions to current active 
grants. Administrative supplements were awarded to current active 
grants that had been previously peer reviewed. 

* Availability of funding--the number of extramural grant applications 
that could receive Recovery Act funding was determined by the funding 
available to each IC, which was specified by the Recovery Act to be in 
proportion to each IC's fiscal year 2009 appropriation. 

* Relevance to scientific priorities--grant applications were 
evaluated to determine their relevance to the scientific priorities of 
the awarding IC. 

In addition to the three standard NIH criteria, the three ICs we 
reviewed considered three additional criteria established by NIH-- 
geographic distribution of Recovery Act funds, the potential for job 
creation, and the potential for scientific progress within 2 years. 
Guidance by the OD to all ICs encouraged--but did not require--the ICs 
to consider these three criteria when making Recovery Act funding 
decisions. The guidance identified the following: 

* Geographic distribution of the Recovery Act funds--ICs were 
encouraged to consider making awards to grantees in states in which 
the aggregate success rate for applications to NIH has historically 
been low.[Footnote 28] NIH encouraged this geographic distribution in 
order for NIH Recovery Act funds to have the widest effect across the 
nation and help state and local fiscal stabilization. 

* Potential for job creation--ICs were also encouraged to consider 
funding extramural grant applications that had the potential to 
preserve and create jobs--a main purpose of the Recovery Act. In 
evaluating applications for administrative supplements, one of the ICs 
we reviewed gave preference based in part on the number of jobs the 
supplement was projected to create or retain. 

* Potential for making scientific progress in 2 years--ICs were 
encouraged to select grant applications for Recovery Act funding in 
instances where IC officials determined that the applicant had the 
potential to make scientific progress within a 2-year period, as 
opposed to the longer duration grant. 

NIH's Recovery Act Grant Awards Varied across Grant Categories and 
Other Characteristics, and NIH Made Information about the Grants and 
Grantees Publicly Available: 

NIH's Recovery Act extramural grant awards varied across three 
categories--awards for applications that had previously been reviewed 
but had not received funding, awards for new grant applications, and 
awards for administrative supplements and competitive revisions to 
current active grants. These awards also varied in size, duration, and 
research methods, with grantees clustered in certain states and 
cities. NIH and the ICs communicated a variety of information to the 
public about the grant awards--including information about grantees--
through NIH's Web sites. 

NIH Recovery Act Grant Awards Varied across Grant Categories, with 
Further Variation in the Specific Distribution of Awards at Selected 
ICs: 

GAO's analysis of NIH data show that NIH Recovery Act grant awards 
varied across three grant categories, with significant further 
variation in the specific distribution of awards across these three 
grant categories at the three ICs we reviewed. As of April 2010, NIH 
used about $7 billion of its $8.6 billion in Recovery Act scientific 
research funds and CER funds to make over 14,000 extramural grants 
awards.[Footnote 29] Specifically, NIH used nearly $2.7 billion of 
Recovery Act funding for grant applications that had previously been 
peer reviewed by NIH but had not received NIH funding; slightly over 
$2.4 billion for new grant applications received from Recovery Act 
funding announcements; and about $1.9 billion for administrative 
supplements and competitive revisions to current active grants. 
[Footnote 30] 

The distribution of Recovery Act awards among the three categories of 
extramural grants varied significantly across the three ICs we 
reviewed. For example, we found that as of April 2010, NIAID used 69 
percent of its Recovery Act funds for existing grant applications that 
had not previously received NIH funding, while NCI used 31 percent of 
its Recovery Act funds for existing grant applications that had not 
previously received NIH funding. In contrast, NHLBI used 51 percent of 
its Recovery Act funds for new grant applications from Recovery Act 
funding opportunity announcements, while NIAID used 5 percent of its 
Recovery Act funding for new grant applications. (See fig. 1 for 
distribution of Recovery Act awards among the three categories of 
grants at the three ICs we reviewed.) 

Figure 1: Selected ICs' Recovery Act Extramural Grant Awards, as of 
April 2010: 

[Refer to PDF for image: 3 pie-charts] 

National Cancer Institute (NCI): 
Existing grant applications that had not previously received NIH 
funding[A]: $260,976,917 (31%); 
New grant applications from Recovery Act funding opportunity 
announcements[B]: $254,845,800 (30%); 
Administrative supplements and competitive revisions to current active 
grants[C]: $325,964,429 (39%). 

National Heart, Lung, and Blood Institute (NHLBI): 
Existing grant applications that had not previously received NIH 
funding[A]: $318,36,600 (37%); 
New grant applications from Recovery Act funding opportunity 
announcements[B]: $437,577,955 (51%); 
Administrative supplements and competitive revisions to current active 
grants[C]: $94,389,325 (11%). 

National Institute of Allergy and Infectious Diseases (NIAID): 
Existing grant applications that had not previously received NIH 
funding[A]: $559,823,392 (69%); 
New grant applications from Recovery Act funding opportunity 
announcements[B]: $38,716,989 (5%); 
Administrative supplements and competitive revisions to current active 
grants[C]: $215,658,047 (26%). 

Source: GAO analysis of NIH data. 

[End of figure] 

Notes: Data from NIH are for extramural grants that have been awarded 
using Recovery Act funds as of April 9, 2010. Percentages may not add 
to 100 because of rounding. In cases where Recovery Act funds 
appropriated to and retained in the OD were used for extramural grants 
that were administered by an IC, we classified the grant and 
associated funding under the administering IC. 

[A] These applications had been submitted for funding from NIH annual 
(non-Recovery Act) appropriations in fiscal years 2008 or 2009, and 
had already been reviewed using NIH's peer review process. 

[B] Recovery Act funding announcements are publicly available 
documents used by NIH to announce an intention to award discretionary 
grants, usually through a competitive process. 

[C] Administrative supplements award additional funds during the 
current project period to an existing extramural grant award that was 
previously peer reviewed--for example, by allowing grantees to add 
personnel or purchase additional equipment. All additional costs must 
be within the scope of the peer reviewed and approved project. 
Competitive revisions are funds added to existing extramural grant 
awards in order to support new research objectives or other changes in 
scope. Like the original grant award to which they are added, 
competitive revisions are awarded using NIH's peer review process. 

[End of figure] 

NIH Recovery Act Extramural Grants Varied in Award Size, Award 
Duration, and Research Methods, and Grantees Were Clustered in Certain 
States: 

GAO's analysis of NIH data also show that as of April 2010, the 14,152 
extramural grant awards NIH made with Recovery Act funds varied in the 
size of the grant award, award duration, and research methods, with 
grantees clustered in certain states, cities, and universities. (See 
app. I for illustrative examples of 45 extramural grant awards made 
with Recovery Act funds.) 

Grant Award Size: As of April 2010, we found that the average Recovery 
Act extramural grant award was slightly more than $492,000, while 
about 25 percent of grants were awarded $623,000 or more. The median 
size of Recovery Act grant awards was nearly $250,000, and Recovery 
Act grant awards ranged in amount from $3,000 to about $29.6 
million.[Footnote 31] NIH awarded 1,259 Recovery Act extramural grants 
of $1 million or more, of which 86 were for $5 million or more. 

Award duration: According to NIH officials, most Recovery Act 
extramural grants were for durations of 2 years or less at the three 
ICs we reviewed, but a few Recovery Act extramural grants were for 
durations longer than 2 years.[Footnote 32] ICs generally limited 
their Recovery Act extramural grant durations to 2 years or less in 
order to fund these grants with Recovery Act funding, which is 
available for obligation until September 30, 2010. However, NIH 
granted ICs the flexibility to fund longer-term extramural grants 
using Recovery Act funds for the first 2 years and annual 
appropriations for additional years, if the grant is consistent with 
the IC's priorities.[Footnote 33] For example, officials at one IC 
reported that because some early-stage principal investigators may 
require more than 2 years to demonstrate success in their chosen field 
of study, the IC offered longer-term awards to these investigators 
that were partially funded with Recovery Act funds and that it expects 
will be partially funded in subsequent years with annual 
appropriations.[Footnote 34] 

NIH officials explained that a potential "cliff effect," or sharp 
reduction in application success rates--the percentage of grant 
applications that receive NIH grant funding--could result beginning in 
fiscal year 2011 when Recovery Act funds are no longer available for 
grants. According to NIH officials, the "cliff effect" could 
potentially occur in two ways. First, recipients of 2-year Recovery 
Act awards may apply for additional funding to extend their projects-- 
potentially increasing the number of grant applications in future 
years. Second, officials at two of the ICs we reviewed reported that 
they committed to supporting grants for a duration longer than 2 years 
using annual appropriations in fiscal year 2011, which may reduce the 
amount of funds that will be available to make new grant awards. NIH 
officials reported that the possible increase in applications 
resulting from the completion of the Recovery Act awards will be 
staggered across the next few years, and one official reported that 
the agency will continue to make decisions about funding research that 
meet their standard criteria. 

Research Methods: NIH officials reported that NIH used Recovery Act 
funds to make grants for projects with a variety of research methods, 
such as clinical trials.[Footnote 35] NIH officials also reported that 
while NIH does not track all forms of research methods, the research 
methods used in connection with the over 14,000 extramural grants 
awarded using Recovery Act funds were similar to the research methods 
used in connection with the extramural grants funded using annual 
appropriations. The officials explained that the data available for 
fiscal year 2009 indicate that extramural research grants funded under 
the Recovery Act had similar research methods, and were awarded in 
roughly the same proportions as extramural grants funded with annual 
appropriations. 

NIH officials also reported that the agency has no general policy 
regarding which scientific methods should be supported using Recovery 
Act funds or annual appropriations, and that NIH left these decisions 
to the ICs. Officials at one IC reported that the IC excluded grant 
applications involving long-term clinical trials using human subjects 
or long-term studies involving animal subjects from consideration for 
Recovery Act funding because Recovery Act funding was generally used 
for shorter-term grants--that is, grants where the specific aims or 
scope could be accomplished within the 2-year duration of the award. 

Geographic distribution: Consistent with the pattern of grants funded 
with annual appropriations in fiscal year 2009,[Footnote 36] the NIH 
Recovery Act grantees were clustered in certain states. Of the over 
14,000 Recovery Act extramural grants awarded as of April 2010: 

* six states--California, Massachusetts, New York, North Carolina, 
Pennsylvania, and Texas--accounted for 50 percent of awards; 

* six cities--Baltimore, Boston, Los Angeles, New York, Philadelphia, 
and Seattle--accounted for over 25 percent of awards; and: 

* five universities received over 10 percent of awards--Duke 
University, Johns Hopkins University, University of Michigan at Ann 
Arbor, University of Pennsylvania, and University of Washington. 

NIH Posted a Variety of Information about Recovery Act Extramural 
Grants and Grantees on Its Web Site: 

NIH communicated various information to the public about the 
extramural grant awards it made using Recovery Act funds.[Footnote 37] 
Information on Recovery Act extramural grant awards was communicated 
to the public through existing and new Recovery Act-specific Web 
pages.[Footnote 38] For example, NIH made information about Recovery 
Act extramural grants available through its existing Research 
Portfolio Online Reporting Tools (RePORT) system, an NIH Web-based 
reporting tool.[Footnote 39] The RePORT system contains information on 
both Recovery Act and non-Recovery Act extramural grants. For example, 
the site includes reports,[Footnote 40] analysis, and data on NIH 
research activities, such as the fiscal year of the award, the 
location of grantee, and awarding IC.[Footnote 41] (See app. I for 
extracts of information provided by NIH about extramural grants that 
were awarded Recovery Act funds, including information from NIH's Web 
Site.) 

In addition to the existing Internet Web sites, NIH and the ICs also 
developed Recovery Act-specific pages on their Web sites to 
disseminate information about Recovery Act grants, including 
extramural grants. For example, NIH highlighted information on 
Recovery Act-funded extramural grants--on major topics of interest to 
the public and groups involved in biomedical research funding--
available through NIH Recovery Act reports on NIH's Internet Web site. 
[Footnote 42] NIH and the ICs posted background stories on particular 
projects and principal investigators on their Web sites.[Footnote 43] 
NIH also made press releases available about Recovery Act-funded 
projects through the NIH Recovery Act news releases page on its Web 
site.[Footnote 44] 

Agency Comments: 

A draft of this report was provided to HHS for review and comment. HHS 
provided technical comments that were incorporated as appropriate. 

As arranged with your offices, unless you publicly announce its 
contents earlier, we plan no further distribution of this report until 
30 days after its issue date. At that time, we will send copies of 
this report to other interested congressional committees, the 
Secretary of HHS, and the Director of NIH. This report will also be 
available on the GAO Web site at [hyperlink, http://www.gao.gov]. 

If you or your staff have any questions regarding this report, please 
contact Linda T. Kohn at (202) 512-7114 or kohnl@gao.gov. Contact 
points for our Offices of Congressional Relations and Public Affairs 
may be found on the last page of this report. Key contributors to this 
report are listed in appendix II. 

Signed by: 

Linda T. Kohn: 
Director, Health Care: 

[End of section] 

Appendix I: Illustrative Examples of NIH Recovery Act Extramural 
Grants: 

The 45 grants presented below include a sample of 15 extramural grants 
awarded with American Recovery and Reinvestment Act of 2009 (Recovery 
Act) funds from each of the three Institutes and Centers (IC) we 
reviewed--National Cancer Institute (NCI), National Heart, Lung, and 
Blood Institute (NHLBI), and National Institute of Allergy and 
Infectious Diseases (NIAID).[Footnote 45] For each IC, the 15 grants 
were randomly selected from the three different categories of grant 
applications--new grant applications from Recovery Act funding 
opportunity announcements, existing grant applications that had not 
previously received National Institutes of Health (NIH) funding, and 
administrative supplements and competitive revisions to current active 
grants. The number of grants selected in each grant category was in 
proportion to the amount of Recovery Act funding awarded for each 
category by the IC, and are not representative of all Recovery Act 
extramural grant awards.[Footnote 46] Grants were assigned categories 
as follows: 

* New applications--New grant applications from Recovery Act funding 
opportunity announcements. 

* Existing applications--Existing grant applications that had not 
previously received NIH funding. 

* Supplements and revisions--Administrative supplements and 
competitive revisions to current active grants. 

The information presented in this appendix about each of the Recovery 
Act extramural grants was provided by NIH. In particular, the grant 
project titles, administering IC, grantee organization, and abstract 
descriptions were reprinted from information supplied by NIH. We did 
not edit them in any way, such as to correct typographical or 
grammatical errors in the abstract descriptions. We calculated the 
grant award size[Footnote 47] reported for each of the 45 grants from 
NIH information on Recovery Act funds. The grant awards ranged from 
about $13,000 to about $7.2 million. 

Grant project title 1: CSHL Molecular Target Discovery and Development 
Center; 
Administering IC: National Cancer Institute; 
Grant award size:$4,737,965.
Grantee organization: 
Cold Spring Harbor Laboratory: 
P.O. Box 100: 
Cold Spring Harbor, NY 11724.
Grant category: New applications; 
Abstract description: In this application we describe our plans to 
create a Molecular Target Discovery and Development Center (MTDDC) 
that will act as downstream component of The Cancer Genome Atlas 
(TCGA) project. Our premise is that the complexity of cancer genome 
alterations leads directly to the heterogeneity of cancer behavior and 
outcome, and that to translate the wealth of cancer genome 
characterization into clinical utility requires the functional 
identification and validation of the underlying driver genes. Driver 
gene identification will lead to a deeper understanding of cancer 
genotypes, create an important new set of biomarkers and therapeutic 
targets, and when combined with genome-wide RNAi screens, lead to the 
identification of key genetic vulnerabilities that will serve as a new 
generation of therapeutic targets. Our planned center is a natural 
expansion of long-standing collaborative projects at Cold Spring 
Harbor Laboratory (CSHL) and combines several powerful methods that we 
have developed and will continue to build upon as outlined in this 
application. These methods include flexible mouse models based on the 
transplantation of genetically-manipulated progenitor cells into the 
appropriate tissues of recipient mice; novel bioinformatics that take 
complex cancer genome datasets and pinpoint candidate driver genes and 
considerably altered pathways; new RNAi technology to manipulate the 
expression of candidate target genes in vitro and in vivo; and genome- 
wide RNAi screens to find genetic vulnerabilities of cancer cells. The 
CSHL MTDDC will use these innovative tools to place the complex array 
of genomic alterations identified by cancer genome projects into 
biologic context. High-throughput screening in mouse models will be 
used to determine whether candidate genes are drivers or passengers. 
Additionally, through the identification of those driver genes that 
are required for tumor maintenance and by genome-wide RNAi screens to 
find the druggable vulnerabilities of major cancer genotypes, we will 
discover and validate a new generation of cancer drug targets. The 
resultant data, reagents, and newly validated biomarkers and targets 
will be openly shared among the TCGA network and broader cancer 
research communities, as we have done with RNAi Codex, CSHL's open- 
access portal/database for short-hairpin RNA (shRNA) gene-silencing 
constructs. 

Grant project title 2: Supporting New Faculty Recruitment Through 
Biomedical Research Core Center; 
Administering IC: National Cancer Institute; 
Grant award size: $1,439,136; 
Grantee organization:
University of Kentucky; 
109 Kinkead Hall; 
Lexington, KY 40506-0057;
Grant category: New applications; 
Abstract description: The strategic plan of the University of Kentucky 
(UK) P30 application in response to RFA-OD-09-005 is to provide 
support for the recruitment of 2 junior investigators who will be 
immersed into a highly collaborative, interdisciplinary group of 
investigators focused on the diagnosis, prevention and treatment of 
gastrointestinal (GI) cancers. This productive group consists of basic 
and clinical scientists, including molecular and cell biologists, 
clinician-scientists (surgeons, gastroenterologists, and medical 
oncologists), GI pathologists, epidemiologists, biostatisticians and 
investigators in the School of Pharmacy with successful programs in 
drug design and delivery. The purpose of this program is to support 
promising junior investigators who will participate in translational 
GI cancer research projects as part of our recently-funded P20 program 
(P20 CA127004) which provides support for the development of a fully- 
funded P50 GI cancer SPORE application. Our goal is to develop a cadre 
of future GI cancer investigators who can participate at the 
intersection of molecular biology, drug discovery and clinical care to 
become leaders in integrative and team approaches to understand the 
complex issues of GI cancer as it relates to potential prevention and 
treatment strategies. This proposal builds upon the momentum and 
existing strengths at the Markey Cancer Center and is further 
supported by substantial institutional, state and philanthropic 
support. 

Grant project title 3: Targeting PTEN Null Tumors via Inhibition of 
the p110beta Isoform of PI3 Kinase; 
Administering IC: National Cancer Institute; 
Grant award size: $1,995,664; 
Grantee organization: 
Dana-Farber Cancer Institute: 
44 Binney St: 
Boston, MA 02115; 
Grant category: New applications; 
Abstract description: The class IA phosphatidylinositol 3 kinase 
(PI3K) signaling axis is perhaps the most frequently activated pathway 
in human cancer. In response to the activation of receptor tyrosine 
kinases (RTKs), G-protein coupled receptors (GPCRs) or Ras, class IA 
PI3Ks, consisting of three catalytic isoforms termed p110?, p110? and 
p110?, are activated to generate the primary intracellular lipid 
signal, phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is 
essential for multiple cellular processes. The tumor suppressor PTEN, 
a lipid phosphatase, dephosphorylates PIP3, thereby antagonizing the 
actions of PI3K and regulating the PI3K pathway activity. Pathway 
activation in tumors is most commonly achieved through activating 
mutations in p110? isoform or via loss of the PTEN tumor suppressor. 
Importantly, PI3K enzymes are highly suited for pharmacological 
intervention, making them attractive targets for cancer therapy. In 
fact, there are a number of PI3K inhibitors from major pharmaceutical 
companies that have entered clinical trials for cancer treatment, but 
most of these inhibitors target all p110 isoforms, which may cause 
side effects arising from the essential roles of PI3K in normal 
physiology. While isoform specific inhibitors are being further 
developed, most of which are directed toward p110? (for solid tumors) 
or p110? (Hematological malignancies). We believe that the drug 
companies have blundered by failing to develop p110?-specific 
inhibitors. We and others have recently demonstrated that tumors 
driven by PTEN loss are specifically dependent of p110? not p110?. The 
broad goal of this project is to generate p110? -specific inhibitors 
for use as new, targeted therapeutics in diverse cancers featuring 
PTEN mutations. To this end we have assembled a team of scientists 
optimized to achieve this goal. Our team's unique reagents for 
assessing PI3K signaling, coupled with and our expertise in protein 
chemistry, X-ray crystallography, medicinal chemistry and animal 
models, position us to effectively develop p110? inhibitors over a two-
year time period for future clinical trials. Our specific goals are to 
generate cell-based systems and genetic models to determine the role 
of p110? in tumorigenesis driven by PTEN in different tissue types and 
to test p110? - specific inhibitors, to purify large amounts of active 
p110? for enzyme assays and crystallography and to pursue a chemistry 
campaign to design and evaluate new scaffolds for p110? inhibition and 
optimize 2 of these scaffolds using both cell and animal models and 
structural information from a complex of p110? and an inhibitor. 

Grant project title 4: Role of TIEG1 in Foxp3+Treg development and 
tumor progression; 
Administering IC: National Cancer Institute; 
Grant award size: $999,094; 
Grantee organization: 
Wayne State University: 
Sponsored Program Administration: 
Detroit, MI 48202: 
Grant category: New applications; 
Abstract description: Although tumor vaccines can induce CD4 helper 
and CD8 cytotoxic response against tumor antigens, they have been 
largely ineffective in causing tumor regression in the clinic. This is 
because the tumor cells acquire many mechanisms to evade the immune 
surveillance program of the host. Foxp3+CD4 +CD25+Treg-mediated immune 
suppression has emerged as one of the crucial tumor immune evasion 
mechanisms and main obstacle of successful tumor immunotherapy. Most 
malignant cells including prostate cancer cells secret large amounts 
of TGF-¿ and has been shown to convert the effector T cells into tumor 
antigen specific Tregs by inducing Foxp3 expression. Such tumor 
induced Tregs not only suppress the priming and effector function of 
anti-tumor effector cells but also form a broad network of self-
amplifying immunosuppressive network. Therefore, overcoming tumor 
induced expansion and de novo generation of Tregs is critically 
important for the design of effective immunotherapeutic strategies for 
successful cancer treatment. We have demonstrated a critical role of 
TGF-¿ inducible early gene-1 (TIEG1) in the transcriptional regulation 
of Foxp3 in CD4T cells treated with TGF-¿. E3 ligase Itch-mediated 
monoubiquitination is essential for nuclear translocation, and 
transcriptional activation of TIEG1. However, in transient 
overexpression systems Itch targets TIEG1 for both mono and 
polyubiquitination. Our preliminary studies suggest that IL-6 which 
inhibits TGF-¿ induced Foxp3 expression induces proteasomal 
degradation of TIEG1 possibly through polyubiquitination. Tyk2-
mediated phosphorylation of TIEG1 seems to act as a recognition signal 
for polyubiquitination of TIEG1. Therefore, we hypothesize that Itch 
targets TIEG1 differentially for mono and polyubiquitination when the 
CD4T cells are stimulated with TGF-¿ or IL-6 and regulates its 
activation and degradation. Despite the growing body of data on the 
role of Foxp3 in Treg development and function, how Foxp3 
transcription is regulated is not clear. We have identified consensus 
NFAT and TIEG1 binding sites adjacent to each other on Foxp3 promoter. 
Since, most transcription factors work cooperatively with other 
factors binding in close proximity we hypothesize that NFAT and TIEG1 
interact on Foxp3 promoter and regulate chromatin remodeling and Foxp3 
expression. A clear understanding of molecular combinations and cross-
talks that imprint Foxp3 transcription in CD4T cells will aid in 
designing strategies to disrupt the inhibitory network of Tregs in 
tumor microenvironment. Using prostate cancer TRAMP-C2 cells which 
secrete large amount of TGF-¿, we will analyze the effect of TIEG1 
deficiency on Treg development and tumor progression. Since TIEG1 does 
not effect nTreg development in the thymus, targeting TIEG1 is an 
appealing strategy to block the de novo induction of Tregs. Such a 
strategy is expected to eliminate most potent tumor specific Tregs 
that inhibit anti-tumor immune response without the risk of triggering 
autoimmunity. 

Grant project title 5: Cell Polarity in Self-renewal and 
Differentiation of Stem/Progenitor Cells: 
Administering IC: National Cancer Institute; 
Grant award size: $713,042; 
Grantee organization: 
Fred Hutchinson Cancer Research Center: 
Box 19024: 
1100 Fairview Ave N: 
Seattle, WA 98109-1024; 
Grant category: Existing applications; 
Abstract description: Self-renewal and differentiation are fundamental 
characteristics of all stem/progenitor cells. During mammalian 
development stem/progenitor cells use cell polarity mechanisms to 
divide asymmetrically to renew themselves and generate daughters that 
stop proliferation and differentiate. Similar mechanisms are used for 
self-renewal and differentiation of adult stem cells. Failure of 
asymmetric cell divisions in stem cells may result in inability to 
withdraw from cell cycle, perturbations of normal brain development 
and cancer. Alternatively, failure of stem cell self-renewal can cause 
depletion of stem cells, decline in tissue regenerative potential and 
premature aging. The molecular mechanisms governing cell polarity and 
asymmetric cell divisions of mammalian stem/progenitor cells and their 
role in aging and cancer are still poorly understood. This proposal 
focuses on cell polarity proteins, Lethal giant larvae 1 and 2 (Lgl1 
and Lgl2), which represent the mammalian orthologs of Drosophila 
neoplastic tumor-suppressor protein Lgl. We have evidence that Lgl1 is 
necessary for regulation of asymmetric cell division of neural 
progenitor cells during early neurogenesis and loss of Lgl1 results in 
abnormal accumulation of progenitors that fail to withdraw from the 
cell cycle. Neonatal death of Lgl1-/-mice precluded us from the 
analysis of potential tumor-suppressor role of Lgls in adult animals 
and their role in self-renewal of adult stem cells. In this proposal 
we will use a variety of conditional gene knockout and biochemical 
approaches to investigate the potential in vivo role and significance 
of the entire Lgl gene family and molecular mechanisms responsible for 
function of Lgl proteins in regulation of stem/progenitor cell self-
renewal and differentiation. These studies will help to extend our 
knowledge of the mechanisms of self-renewal and differentiation of 
mammalian stem/progenitor cells. This information will be useful for 
future development of efficient regenerative, anti-aging and 
anticancer therapies. 

Grant project title 6: Human CYP2A and respiratory tract xenobiotic 
toxicity: 
Administering IC: National Cancer Institute; 
Grant award size: $663,881; 
Grantee organization:
Wadsworth Center Health Research, Inc. 
Menands, NY 12204-2719:
Grant category: Existing applications; 
Abstract description: The long-term objective is to determine the role 
of respiratory tract cytochrome P450 (P450 or CYP) enzymes in target 
tissue metabolic activation and toxicity of environmental chemicals. 
Our focus continues to be on CYP2A13, an enzyme selectively expressed 
in human respiratory tract, and the most efficient human P450 enzyme 
in the metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone (NNK), a major tobacco-derived respiratory tract 
procarcinogen. CYP2A13 is also known to metabolize numerous other 
important respiratory tract toxicants. Our hypothesis, that CYP2A13 
plays an important role in tobacco-related lung carcinogenesis in 
humans, is supported by findings of a recent epidemiological study, 
and by reports confirming that CYP2A13 protein is expressed in human 
lung, where it is active in the metabolic activation of NNK, and that 
P450s in the lung, but not those in the liver, are essential for NNK-
induced lung tumorigenesis in mouse models. Furthermore, our 
preliminary finding, that expression of CYP2A13 is downregulated by 
inflammation, offers an explanation for why the levels of CYP2A13 
protein detected in patient-derived lung biopsy samples were so low, 
and suggests the possibility that CYP2A13 levels in intact, healthy 
lungs are much higher. Here, we propose three series of experiments to 
overcome the difficulties associated with not being able to directly 
study P450 expression or activity in intact, healthy human lungs. We 
will (1) study a CYP2A13-humanized mouse model, in order to provide 
proof-of-principle for the potential of CYP2A13 to mediate NNK-induced 
lung tumorigenesis in humans; (2) perform additional studies to better 
understand the nature and scope of inflammation-induced suppression of 
CYP gene expression in the lung; and (3) identify common CYP2A13 
genetic variants that cause changes in gene expression (and the 
underlying mechanisms), in order to provide biological basis for 
future epidemiological studies aimed at further confirming the role of 
CYP2A13 in smoking-induced lung cancer or other chemical toxicities in 
various ethnic or occupational groups. We believe that our proposed 
studies are novel, and the anticipated outcome will be highly relevant 
to mechanisms of chemical carcinogenesis and other chemical toxicities 
in human lung. 

Grant project title 7: Sentinel Node Versus Axillary Dissection in 
Breast Cancer; 
Administering IC: National Cancer Institute; 
Grant award size: $1,498,205; 
Grantee organization:
University of Vermont & St Agric College: 
85 South Prospect Street: 
Burlington, VT 05405; 
Grant category: Existing applications; 
Abstract description: The long-term objectives of this proposal are to 
develop and refine methods of breast cancer staging in patients that 
are substantially less morbid than current methods, yet still provide 
the same diagnostic and therapeutic benefits. For the past nine years 
we have partnered with the National Surgical Adjuvant Breast and Bowel 
cooperative group (NSABP) to conduct a large, multi-center, 
randomized, Phase III prospective trial that compares sentinel lymph 
node (SLN) resection to conventional axillary dissection in clinically 
node-negative breast cancer patients (NSABP trial B-32). During the 
last grant period we have also launched a multicenter study to 
investigate whether detection of the presence of bone marrow 
micrometastases provides enhanced and early prediction for survival of 
breast cancer patients (NSABP study BP-59). Several tasks have been 
shared between UVM and NSABP, such as final trial design and protocol 
development. UVM has had non-overlapping primary responsibility for 
the following: (1) training and quality control of all aspects of SLN 
surgery and bone marrow sample procurement; (2) processing and 
interpretation of SLNs for occult metastases; (3) processing and 
interpretation of bone marrow samples for disseminated tumor cells; 
and (4) statistical analysis of the following three relationships: 
firstly, the relationship of training to surgical outcomes and quality 
of reported data; secondly, the relationship of occult metastases in 
SLNs to survival and other patient variables, and thirdly, the 
relationship of bone marrow micrometastases to survival. During the 
time period of this proposal the first 6 Aims will be fully completed 
and the 7th Aim will result in complete specimen accrual and 
interpretation. The Specific Aims of the current active grant are: 
Specific Aims #1 and #2: Determine whether SLN resection alone, when 
compared to ALN dissection plus SLN resection, results in equivalent 
long-term control of regional disease (Aim 1) and disease-free and 
overall survival (Aim 2). Aim #3: Determine the magnitude of morbidity 
reduction of SLN surgery versus ALN resection. Aim #4: Determine the 
magnitude of quality of life improvement by SLN surgery versus ALN 
resection. Aim #5: Determine whether standardized immunohistochemistry 
analysis of hematoxylin and eosin-negative SLNs identifies patients at 
risk for decreased overall and disease-free survival. Aim #6: 
Establish a standardized method of SLN surgery in a large number of 
centers for procedural consistency. Aim #7: Determine the relative 
risk of death associated with the presence of tumor cells in the bone 
marrow of breast cancer patients and investigate the relationship 
between 2 tumor cell detection methods, brightfield and 
immunoflourescence cytochemistry, in detecting bone marrow 
micrometastases. 

Grant project title 8: p53 Acetylation as a Mechanism in 
Chemoprevention by Aspirin: 
Administering IC: National Cancer Institute; 
Grant award size: $148,500; 
Grantee organization: 
Texas Tech University Health Scis Center: 
3601 4th Street - Ms 6271: 
Lubbock, TX 79430-6271; 
Grant category: Existing applications; 
Abstract description: A vast amount of epidemiological, preclinical 
and clinical studies have revealed aspirin as a promising 
chemopreventive agent, particularly in epithelial carcinogenesis. 
Despite the wide attention inhibition of cyclooxygenases has received, 
it is clear that aspirin elicits a myriad of molecular effects that 
counteract the carcinogenic episodes. Since aspirin's protective 
effect was mainly observed in epithelial cell types which are more 
resistant to chemotherapeutic efforts, an urgent need exists to 
dissect and identify the primary targets and cancer preventive 
pathways affected by aspirin. In preliminary studies, we have obtained 
the first and strong evidence for a dose-and time-dependent 
acetylation of p53 tumor suppressor protein by aspirin in MDA-MB-231 
human breast cancer cells, several cancer cells belonging to different 
tumor types and also in normal liver cells. In MDA-MB-231 cells, 
aspirin induced the levels of p53 target genes namely p21CIP1, a 
protein involved in cell cycle arrest, and Bax, a proapoptotic 
protein; however, p21 induction was transient (1-12h); where as, 
induction of Bax was sustained (24 h). Interestingly, in DNA damaged 
cells (induced by camptothecin), aspirin treatment (24 h) inhibited 
the p21 induction, while the Bax induction was unaffected. Built on 
these findings, the central hypothesis of this R03 pilot project is 
that aspirin-induced multi-site acetylation of p53 alters its 
transcription factor function by shifting the gene expression spectrum 
from those that elicit cell cycle arrest/prosurvival properties to 
those that promote and drive cell death. Since deletion of p21 gene 
has been previously shown to increase the sensitivity of cells towards 
apoptosis, our observation that aspirin inhibits p21 suggests a 
potential mechanism by which it may exert anti-cancer effects in DNA 
damaged cells. The studies proposed in this application will determine 
the mechanisms by which aspirin regulates apoptosis in DNA damaged 
cells via inhibition of p21. We will use MDA-MB-231 and MCF-7 breast 
cancer cells as well as normal human Peripheral Blood Mononuclear 
Cells in our study. The experiments in Aim 1 will investigate the 
molecular basis of aspirin-mediated inhibition of p21 using real time 
RT-PCR, electrophoretic mobility shift assays, and run on 
transcription assays. We will also identify aspirin-induced 
acetylation sites on p53. In Aim II, we will determine the ability of 
aspirin to augment apoptosis in cells exposed to DNA damaging drugs by 
clonogenic cell survival assays and flow cytometry. In addition to 
camptothecin, all studies will be extended to include doxorubicin and 
cisplatin, to determine if aspirin also modulates p21/Bax expression 
by these DNA damaging drugs. These studies will provide a novel 
mechanism by which aspirin may exert anticancer effects in DNA damaged 
cells via acetylation of p53, induction of Bax and inhibition of p21. 

Grant project title 9: The role of pheomelanin in cutaneous melanoma: 
Administering IC: National Cancer Institute; 
Grant award size: $630,397; 
Grantee organization: 
Tufts Medical Center: 
800 Washington St: 
Boston, MA 02111-1526: 
Grant category: Existing applications; 
Abstract description: Ultraviolet (UV) radiation represents a 
definitive risk factor for skin cancer, particularly in combination 
with certain underlying genetic traits, such as red hair and fair 
skin. Skin pigmentation results from the synthesis of melanin in 
pigment-producing cells, the melanocytes, followed by distribution and 
transport of the pigment granules to neighboring keratinocytes. 
Epidemiological studies have found less skin cancer in people who have 
high levels of constitutive pigment and/or tan well. However, we have 
incomplete understanding of other factors involved in the development 
of skin cancer, such as capacity to repair photo-damage in people of 
different skin colors. The finding that albinos have a lower incidence 
of melanoma than people with fair skin makes this question more 
complex. Recent findings including our own have led to a realization 
that melanin, especially pheomelanin (a yellow/red form of melanin), 
acts as a potent UVB photosensitizer to induce DNA damage and cause 
apoptosis in mouse skin. The proposed research will focus on the role 
of pheomelanin in DNA damage, at both genomic and individual 
nucleotide levels, and on the subsequent activation of DNA repair, 
alteration in chromatin structure, and ultimately melanoma formation. 
We hypothesize that pheomelanin contributes to UVinduced DNA damage 
that is incompletely repaired. Although DNA repair may be activated to 
a larger extent in response to the greater DNA damage in pheomelanin-
containing skin, the repair will be insufficient to eliminate all 
mutagenic adducts. We will first identify the role of pheomelanin in 
melanoma formation by melanoma mouse models. Second, we will define 
the photoproducts and oxidative stress to DNA in mice with different 
type of epidermal pigmentation at different times after UVB 
irradiation by quantitative methods. Third, we will map DNA damage in 
specific sequences of BRAF and N-RAS genes, both of which are 
frequently mutated in human melanoma. Finally, we will detect the 
expression of genes in DNA repair pathways at different times after 
UVB irradiation. Given the vital role that pheomelanin plays in normal 
phototoxicity and disease, these studies will provide important 
insights into the homeostasis of tanning and the pathogenesis of 
disorders like melanoma. Expanding our knowledge of DNA repair in 
different skin types provides a rich ground for melanoma prevention 
and for the development of targeted small-molecule therapeutics. 

Grant project title 10: Cancers in Older Minority Populations: 
Caribbean American; 
Administering IC: National Cancer Institute; 
Grant award size: $125,720; 
Grantee organization: 
Long Island University: 
Brooklyn Campus: 
1 University Plz: 
Brooklyn, NY 11201-8423; 
Grant category: Supplements and revisions; 
Abstract description: Strong ties have developed between investigators 
at Long Island University's Brooklyn campus (LIU) and Columbia 
University's Herbert Irving Comprehensive Cancer Center (HICCC) over 
the past four years. Several joint grants and projects have resulted, 
totaling over $2 million, with two proposals pending. Anchoring this 
collaboration has been a P20 from NCI (CA91372). These research 
efforts have focused on differences among African Caribbean immigrant 
populations in Brooklyn and North Manhattan (including Dominican, 
Haitian, and English-speaking Caribbeans) and US-born African 
Americans and European Americans. The research includes behavioral, 
cultural, lifestyle, and biological genetic differences that may 
relate to cancer-related health disparities. In this application, we 
propose to build upon the existing partnership and use it as a 
platform for a broader, more comprehensive study of the same issues. 
This partnership would meld the two institutions, with an emphasis on 
bringing together their complementary strengths. The PI at LIU is a 
well-known psychologist with extensive behavioral and survey research 
experience with these populations in Brooklyn. The PI at Columbia is a 
medical oncologist and epidemiologist with a strong record in cancer 
prevention and control research and a leadership position in the MCCC. 
HICCC will provide access to its core facilities, especially the 
Biostatistics Core, while LIU will provide its expertise in survey and 
behavioral research. The proximity of the two institutions will permit 
frequent seminars and workshops attended by individuals from both 
centers, as well as an annual retreat at each center. Students and 
faculty at each will also have access to courses and lectures at each 
of the institutions. Equally important will be programs designed to 
provide experience for minority students and faculty in cancer 
research, with the opportunity for students from LIU to obtain 
admissions and fellowships to Columbia programs, illustrated by a 
minority predoc from LIU who will have a T32 postdoc at Columbia. Two 
projects and four pilots are U54 program. There will be an annual 
competition for funding for the following year; proposals will be 
reviewed by external reviewers, as was successfully conducted in our 
P20. Ongoing/proposed projects/pilots will be I discussed at a monthly 
workshop alternating between campuses at which statisticians, data 
management, and methodologists will attend to provide constructive 
discussion. A representative from the University of West Indies (UWI) 
will attend annual EAB meetings and, via videoconference, quarterly 
internal steering committee meetings with long-term possibilities for 
dual site (Brooklyn/Caribbean) projects. This partnership has a unique 
study population, a successful existing relationship, and an emphasis 
on population science research. 

Grant project title 11: Case Comprehensive Cancer Center Support Grant; 
Administering IC: National Cancer Institute; 
Grant award size: $1,461,630; 
Grantee organization: 
Case Western Reserve University: 
10900 Euclid Ave: 
Cleveland, OH 44106-7015; 
Grant category: Supplements and revisions; 
Abstract description: The Case Comprehensive Cancer Center (Case CCC), 
now in its 17 year, provides leadership and oversight for basic cancer 
research, therapeutic and non-therapeutic cancer clinical trials, 
prevention, control and population research, as well as community 
outreach for the major affiliate institutions of Case Western Reserve 
University: Case School of Medicine, University Hospitals of 
Cleveland, and the Cleveland Clinic. Located in Cleveland and serving 
the 3.8 million people in Northern Ohio, members of the Cancer Center 
manage over 7,000 new cases per year with a high rate of clinical 
trial access and accrual, operating under a single protocol 
development and review system, data safety management plan, and a 
coordinated clinical trials operation. Since the last competitive 
renewal application, the Center has increased NCI funding by more than 
53%, and more than doubled its total peer-reviewed funding. The Center 
also accrued 877 patients to therapeutic clinical trials in 2005. 
Significant institutional commitment to Center development resources, 
faculty recruitment, shared resources, and space assures the Center's 
continued success and its dynamic approach to multidisciplinary cancer 
research and therapeutics. The Case CCC has 9 Scientific Programs, 17 
shared resources including 6 that are new, and a clinical and 
behavioral cancer research infrastructure that prioritizes innovative 
translational research and investigator-initiated clinical trials that 
cut across the Scientific Programs. These programs include Cancer 
Genetics, Cell Proliferation and Cell Death, Radiation and Cellular 
Stress Response, Molecular Mechanisms of Oncogenesis, GU Malignancies 
(new), Stem Cells and Hematologic Malignancies, Developmental 
Therapeutics, Cancer Prevention, Control and Population Research, and 
Aging-Cancer Research (new). The new Shared Resources include Imaging 
Research, Proteomics, Hybridoma, Transgenic & Targeting, Translational 
Research, and Practice-Based Research Network. Each of these new 
Shared Resources is fully operational, supporting the cancer research 
of multiple members across programs, and providing a critical platform 
for multidisciplinary and interdisciplinary research. This scientific 
organization and infrastructure furthers the mission of the Case CCC: 
to improve the prevention, diagnosis, and therapy of cancer through 
discovery, evaluation, and dissemination that together reduce cancer 
morbidity and mortality in Northern Ohio and the Nation. 

Grant project title 12: Spin Probes in Semipermeable Nanospheres: EPR 
spectroscopy & imaging of tumor pH: 
Administering IC: National Cancer Institute; 
Grant award size: $51,972; 
Grantee organization: 
Ohio State University: 
1960 Kenny Road: 
Columbus, OH 43210; 
Grant category: Supplements and revisions; 
Abstract description: The overall goal of this project is to develop 
new functional EPR probes of enhanced stability for in vivo EPR 
spectroscopy and imaging of pH, one of the most important parameters 
in the biochemistry of living organisms. pH-sensitive nitroxyl 
radicals have been previously developed by the P.I. and colleagues but 
often suffer insufficient stability in living tissues. In this project 
two different strategies will be used to develop paramagnetic probes 
with stability in vivo based on the original idea of constructing nano-
Sized Particles with the Incorporated Nitroxides, or nanoSPINs. The 
semipermeable membrane of the nanoSPINs will differentiate sensing 
nitroxides from biological reductants while allowing free penetration 
of the analyze, H+. This will fill a niche between fluorescent pH 
probes, which have provided advances in applications for cellular and 
subcellular detection, and NMR/MRI, which have provided applications 
in living animals and humans, but these current techniques often 
suffer from the lack of sensitivity (1000 fold or lower than EPR) and 
specificity. The specific aims are: (SA1) To develop effective 
approaches for the design of pH-sensitive nanoSPINs. Two alternative 
strategies for the incorporation of the nitroxides into semipermeable 
nanospheres will be used, namely incorporation into phospholipids 
liposomes and polyamide capsules. (SA2) To define spectroscopic and 
physicochemical characteristics of pH-sensitive nanoSPINs. 
Quantitative characterization of the obtained nanoSPIN is absolutely 
crucial both for the optimization of the preparation procedures and 
for efficiency of their further applications. (SA3) To apply in vivo 
EPR measurements of pHe in PyMT tumor-bearing mice using developed 
nanoSPINs. The measurement of the extracellular pHe in the PyMT 
mammary tumors in living mice using developed pH-sensitive nanoSPINs 
will provide new insights into related biochemical processes, 
including better understanding of the observed anti-tumor activity of 
Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), a 
therapeutic approach which is currently of much interest. The results 
may provide an opportunity for the design of other corresponding 
therapeutic approaches. In summary, the success of this project may 
have a significant impact on the future of functional in vivo EPR 
spectroscopy and bioimaging applications to medicine. This project 
will develop pH-sensitive paramagnetic probes of enhanced stability 
based on encapsulation of the nitroxides into semipermeable 
nanospheres. These probes, termed nanoSPINs, will allow in vivo EPR 
spectroscopy and imaging of pH. The experiments using pH-sensitive 
nanoSPINs in PyMT mammary tumors in living mice are planned to 
contribute to the understanding of the mechanisms of extracellular 
acidosis in solid tumors and to use extracellular pH to monitor tumor 
progression and thus evaluate the efficacy of anti-tumor drugs, and 
provide opportunities for designing corresponding therapeutic 
approaches. 

Grant project title 13: Development of Oncomine Professional as a 
Platform for Biopharmaceutical Research; 
Administering IC: National Cancer Institute; 
Grant award size: $263,987; 
Grantee organization: 
Compendia Bioscience, Inc. 
Floor 2: 
Ann Arbor, MI 48104: 
Grant category: Supplements and revisions; 
Abstract description: DNA microarray studies, largely sponsored by the 
NIH and other granting agencies, have generated a wealth of data 
uncovering the complex gene expression patterns of cancer. Currently 
however, there is no unifying organizational or bioinformatics 
resource to integrate the myriad independent observations into a 
single, global, computable environment. Such a resource would not only 
provide wide access to data from individual studies, but would also 
provide an opportunity to apply advanced analysis techniques to the 
aggregated data. In the absence of such a resource, the majority of 
cancer molecular profiling data remains severely under-utilized by 
both the academic cancer research community, and by the pharmaceutical 
and biotechnology companies who could utilize this data to aid in 
their efforts to develop new biomarkers and therapies. We propose to 
develop a commercial scale solution for cancer molecular profiling 
research to address this problem. The solution builds upon the 
prototype of Oncomine developed at the University of Michigan, which 
utilizes a data pipeline, a data warehouse, an analysis engine, and a 
web interface to deliver human cancer genomic data in an intuitive 
platform to scientists and clinicians. The specific aims in Phase I of 
this proposal are to: 1. Modify the Academic Data Pipeline to Support 
Commercial Operations. 2. Re-host and re-structure the Oncomine 
Database. 3. Develop a commercial technical operating model for the 
Oncomine Web Application. In Phase II of this proposal we will: 1. 
Develop a controlled cancer genomics data pipeline to support the 
rapid and proactive collection, standardization and analysis of 
heterogeneous cancer genomics data from repositories, academic 
laboratories and pharmaceutical companies. 2. Develop a scalable and 
secure cancer genomics data warehouse to support the storage and 
retrieval of public and proprietary data. 3. Develop an optimized user 
interface to support cancer drug discovery and development. The result 
of this work will be a fully integrated, end-to-end platform for 
providing publicly funded research results to the commercial sector, 
with a goal of utilizing that data to develop new diagnostic and 
therapeutic approaches for treating cancer. The Oncomine prototype is 
already broadly accepted in academia, and has been verified as a 
research tool with high utility by over 10,000+ non-profit users. 
Since 2006 Compendia has worked to establish the commercial merit of 
Oncomine; as a result, tens of thousands of valuable high-throughput 
experiments are now being utilized by several of the world's top 
pharmaceutical companies. However, additional funding is required to 
transition Oncomine from an academic tool to a commercial platform, 
and to realize the full commercial potential of this approach to 
advance research and save lives.Cancer is a leading cause of 
mortality, and is responsible for one in every four deaths in the 
United States. In recent years global gene expression technologies 
have generated important new information about the molecular 
mechanisms underlying cancer by revealing specific aberrations in 
genes, proteins, and signaling pathways. This proposal seeks funding 
to provide a platform for aggregating, analyzing, and presenting this 
genomic data to drug development companies, with a goal of optimizing 
the clinical usefulness of cancer genomic data for drug discovery and 
development. 

Grant project title 14: Pharmacogenomics of Childhood Leukemia (ALL); 
Administering IC: National Cancer Institute; 
Grant award size: $661,549; 
Grantee organization: 
St. Jude Children's Research Hospital: 
Memphis, TN 38105; 
Grant category: Supplements and revisions; 
Abstract description: Despite substantial progress in the past two 
decades, cancer remains the leading cause of death by disease in US 
children between 1 and 15 years of age. Acute lymphoblastic leukemia 
(ALL) is the most common childhood cancer, and cure rates are 
approaching approximately 80% today. Unfortunately, 20% of children 
with ALL are not cured with current therapy, making the number of 
cases of relapsed ALL greater than the total number of new cases of 
most childhood cancers. Previous work has established that de novo 
drug resistance is a primary cause of treatment failure in childhood 
ALL. However, the genomic determinants of such resistance remain 
poorly defined. We have recently identified a number of new genes that 
are expressed at a significantly different level in B-lineage ALL 
cells exhibiting de novo resistance to widely used antileukemic agents 
(prednisolone, vincristine, asparaginase, daunorubicin), and their 
pattern of expression was also significantly related to treatment 
outcome. To assess, three research aims that extend our prior 
findings. The first scientific aim is to identify genes conferring de 
novo resistance of childhood ALL to the widely used thiopurines, 
mercaptopurine and thioguanine. This will be the first genome-wide 
analysis of genes conferring thiopurine resistance and will provide 
important new insights into whether they represent distinct 
antileukemic agents. The second aim is to identify genes in T-ALL that 
confer de novo resistance to the four agents we have previously 
studied in B-lineage ALL (prednisolone, vincristine, asparaginase, 
daunorubicin) and the two thiopurines. This will yield pharmacogenomic 
insights into why T-ALL has a worse prognosis with most treatment 
protocols. The final aim is to identify germline polymorphisms or 
epigenetic changes in the promoter regions of those genes that are 
differentially expressed in ALL cells exhibiting resistance to these 
antileukemic agents. Preliminary studies have already identified a 
significant relation between mRNA expression in ALL cells and the 
promoter haplotype structure of the first gene investigated (SMARCB1). 
It is important to extend these pharmacogenomic studies in a 
systematic way to additional genes conferring de novo drug resistance. 
These findings will continue to provide important new insights into 
the genomic determinants of treatment failure and point to novel 
targets for developing strategies to overcome drug resistance in 
childhood ALL. 

Grant project title 15: University of New Mexico Cancer Center Support; 
Administering IC: National Cancer Institute; 
Grant award size: $1,264,145; 
Grantee organization: 
University of New Mexico: 
Main Campus, PreAward: 
Albuquerque, NM 87131; 
Grant category: Supplements and revisions; 
Abstract description: The Cancer Epidemiology and Prevention Program 
was formally established in 1973 when the New Mexico Tumor Registry 
joined with 6 other population-based tumor registries to form the NCI- 
SEER (Surveillance, Epidemiology and End Results) program. The NM SEER 
data provide the fundamental, population-based data for hypothesis 
generation in this program, and has led to a strong base of funding 
for research in lung, breast, skin and GI cancers. The striking 
differences in cancer patterns, in cancer health disparities, and in 
outcomes among New Mexico's multiethnic population are under intense 
investigation to uncover the genetic, environmental, social, and 
behavioral factors that account for these patterns and disparities. In 
addition, the program's community-based research and outreach in 
cancer education, screening, and prevention among rural, American 
Indian and Hispanic populations work toward correcting those 
disparities. Led by co-directors Marianne Berwick and Steven Belinsky, 
the Cancer Epidemiology and Prevention Program joins 23 full members, 
2 members with secondary appointments, and 5 associate members with 
primary appointments in 5 Departments within the UNM School of 
Medicine and College of Pharmacy, the Lovelace Respiratory Research 
Institute, and the Albuquerque Veteran's Administration Medical 
Center. The Cancer Epidemiology and Prevention Program has four major 
scientific goals that cross the organbased themes of lung, breast, 
skin and gastrointestinal cancers: (1) To identify the genetic, 
epigenetic, environmental and behavioral risk factors contributing to 
the development and progression of cancer, particularly those cancers 
that disproportionately affect New Mexico's multiethnic populations; 
(2) To develop biomarkers for the risk factors identified in aim 1; 
(3) To develop interventions for cancer prevention that target 
specific biochemical pathways and factors identified in aim 1, that 
will be assessed using biomarkers from aim 2; and (4) To translate 
these interventions into community prevention, outreach, and education 
programs using community-based participatory research methods. The 
high quality of the interactive research in this Program has resulted 
in a large number of peer-reviewed grants and collaborative 
publications. The Program is supported by $10,374,531 in peer-reviewed 
funds (annual direct costs) from NCI, other NIH, DOD and CDC. Of this, 
$4,225,820 (41%) is NCI funding (exclusive of SEER funding). Program 
Members published 263 cancer-relevant, peer-reviewed articles between 
2000 and 2005; 16% of those represent intra-programmatic collaboration 
and 4% inter-programmatic collaboration. Program members serve in 
national leadership roles in multiple cooperative group initiatives 
and in NIH review panels. The large number of collaborative 
publications, the success at obtaining peer-reviewed funding, and the 
national leadership roles played by Program members document the 
excellence of the interactive efforts of this Program. Major 
programmatic research accomplishments include: the identification of 
epigenetic events, critical to the risk and progression in lung 
cancer; the identification of disparate risk for breast cancer 
prognostic markers between Hispanic and non-Hispanic white women; and 
the demonstration of a protective role for sun exposure in melanoma 
survival that may be due to the metabolism of Vitamin D. These 
findings set new directions for research into the fundamental biology 
of these cancers and will help direct the establishment of biomarkers 
to identify high-risk individuals for intervention. 

Grant project title 16: Supporting New Faculty Recruitment Through 
BioMedical Research Core Center; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $1,119,435; 
Grantee organization: 
University of Minnesota Twin Cities: 
450 McNamara Alumni Center: 
Minneapolis, MN 55455-2070: 
Grant category: New applications; 
Abstract description: The University of Minnesota Pulmonary, Allergy, 
Critical Care & Sleep (PACCS) Division has been systematically 
recruiting additional physician scientists focused on lung injury and 
repair to join the tenure track faculty. Our faculty met and 
identified a significant gap in our faculty research interest profile 
in this area - respiratory infections. This area is not only of great 
importance as a public health issue in the US and worldwide, it is 
also an area with outstanding multi-disciplinary, collaborative 
scientific opportunities at the University of Minnesota. Within the 
PACCS Division, among our NIH-funded PIs, there are 7 faculty with 
expertise in lung inflammation and injury. In addition, there are 
three academically strong Centers and programs pertinent to our 
proposed recruit, providing a dynamic research environment to promote 
scientific growth and career development. The Center for Infectious 
Disease, Microbiology & Translational Research brings together faculty 
from the Medicine, Pediatrics and Microbiology Departments in 
interdisciplinary translational research on microbial pathogenesis. 
The Center for Lung Science and Health provides a home for faculty and 
students from across the Academic Health Center and larger University 
with interests related to lung health and disease. Finally, the 
University of Minnesota has an internationally renowned Cystic 
Fibrosis program. While this program is outstanding in clinical care 
and clinical trials activity, the basic research component is less 
strong. Thus a major recruitment target area of the PACCS Division is 
for a physician-scientist with research focused on respiratory 
infections, particularly with relevance to lung injury in Cystic 
Fibrosis. Our proposed P30 recruit, Bryan Williams MD, PhD is 
completing his fourth year of Pulmonary, Critical Care & CF fellowship 
at Vanderbilt University. His research focus is on host-pathogen 
interactions in respiratory infections, specifically exploring the 
role of a polyamine precursor, agmatine, that is important in 
Pseudomonas infections and in biofilm formation. He obtained his 
Microbiology PhD under the mentorship of Dr. Arnie Smith studying 
Hemophilus infections and his post-doctoral fellowship research has 
been supervised by Dr. Timothy Blackwell. Dr Williams' research 
relates directly to his clinical interest in CF-related lung dise 
disease, enabling convergence of his research and clinical program. 
The recruitment of Bryan Willliams MD, PhD will add the new dimension 
of expertise in respiratory infections to the PACCS Divisional 
research It will greatly augment basic research in the Cystic Fibrosis 
Center program and will provide a research bridge between the Center 
for Lung Science and Health and the Center for Infectious Disease, 
Microbiology Translational Research. Dr Williams's research brings an 
innovative approach to understanding and decreasing Pseudomonas 
infection in CF patients. 

Grant project title 17: Cell Based Therapy for Lung Disease; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $999,999; 
Grantee organization: 
National Jewish Health: 
1400 Jackson Street: 
Denver, CO 80206; 
Grant category: New applications; 
Abstract description: We propose to build a new paradigm for advancing 
and transforming patient care through development of cell-based 
therapies for human lung disease. Analysis of acute lung injury in 
mice indicates that epithelial damage can prestage loss of alveolar 
structure and function. These data support the hypothesis that cell- 
based therapy focused on replacement of the damaged epithelium can 
ameliorate morbidity and mortality associated with high risk diagnosis 
and progression to acute lung injury. Our analysis of lung epithelial 
stem and facultative progenitor cells suggests that the latter cell 
type exhibits optimal characteristics for replacement of injured 
epithelial cells as well as restoration of critical homeostatic 
functions. Based on these studies we propose to use competitive 
repopulation to test the hypothesis that facultative progenitor cells 
can repopulate the injured airway or alveolar epithelium in the 
context of acute lung injury. These hypotheses will be tested using 
functionally distinct populations of human lung facultative progenitor 
cells, basal and the alveolar type II cells. These cell types are 
known to maintain and regenerate the normal bronchial and alveolar 
epithelial compartments. Acute and progressive aspects of acute lung 
injury will be represented using a novel mouse model that 
recapitulates the morbidity and mortality of acute lung injury on post-
treatment days 5 and 10. Previously developed cell isolation methods 
and this unique mouse model will be combined to determine: (1) the 
characteristics of the most promising target patient population for 
cell-based therapy; (2) the best cell type for treatment of early and 
late acute lung injury; and (3) preclinical parameters including 
optimal route, dose, and timing of treatment. Successful completion of 
this study will propel the field of cell replacement therapy for lung 
disease beyond the planning stage and into a position appropriate for 
initiation of clinical trials. The limitations of previous analyses 
will be overcome through implementation of an appropriately powered 
analysis of intersections between time, cell type, route, and dose. 
Trials for refinement of the treatment protocol and evaluation of 
consistency among donor cell populations are advanced components of 
the study design. Outcomes will be evaluated through quantitative 
measurements that are germane to pulmonary function. This novel 
intervention strategy has the potential to ameliorate morbidity and 
mortality in the almost 200,000 American citizens that suffer from 
acute lung injury associated with trauma, aspiration, or infection 
each year. Among these patients there are nearly 75,000 deaths per 
year. This benefit will be achieved through development of new 
treatment strategy and through facilitation of research focused on 
engineering approaches to lung regeneration or replacement. Thus, 
focused evaluation of the fundamental parameters highlighted in this 
pre-clinical trial will advance the emerging field of cell based 
therapy and regenerative medicine approaches to treatment of acute 
lung injury. 

Grant project title 18: Development of an Asthma Research Core Center; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $994,437; 
Grantee organization: 
Children's Hospital Med Ctr (Cincinnati): 
3333 Burnet Ave: 
Cincinnati, OH 45229-3039; 
Grant category: New applications; 
Abstract description: Asthma, a chronic inflammatory disorder of the 
airways, is estimated by the World Health Organization to affect 150 
million people worldwide and its global pharmacotherapeutic costs 
exceed $5 billion per year. Cincinnati Children's Hospital Medical 
Center (CCHMC) provides clinical care to -7000 asthmatic children in 
the primary care and specialty clinics. Last year, over 3000 children 
were treated in the CCHMC Emergency Department with the primary 
diagnosis of an acute asthma exacerbation, and 885 patients (29.5%) 
were admitted to the hospital for management of acute asthma 
exacerbations. CCHMC has invested considerable resources to promote 
asthma research including the establishment of the Division of Asthma 
Research, which has partnered with the Asthma Center to create a 
comprehensive Asthma Program, which now provides a central base for 
the clinical and research activities for asthma at CCHMC. Patients 
suffering from asthma share similar clinical symptoms, but the disease 
is heterogenous in terms of phenotypes and natural history 3, 4. This 
heterogeneity contributes to the difficulty in both studying and 
treating asthma. The heterogeneity in asthma is poorly understood and 
the mechanisms by which genetic and environmental influences impact 
asthma development and asthma disease expression are largely unknown. 
As such, the proposed Asthma Research Core has the central goal of 
improving the understanding of the heterogeneity in asthma. In order 
to accomplish this goal, we propose 2 aims: Aim #1: To recruit or 
promote a new faculty member into the tenure track to develop a 
research program focused a topic relevant to elucidating the 
mechanisms contributing to asthma heterogeneity. Aim #2: To develop a 
pilot research program in Asthma Research to support new faculty in 
the tenure track in the areas outlined above. The frequency of absent 
or incomplete efficacy in asthma treatment is as high as 70%, due to 
the inherent heterogeneity in asthma phenotypes caused by multiple 
genetic and environmental influences. The central goal of this 
proposal is to improve the understanding of the heterogeneity in 
asthma. Improved understanding of asthma phenotypes will enable 
informed personalized treatment plans and likely will result in 
substantial reduction in asthma expenditures. 

Grant project title 19: Genome-Wide Association and Exon Sequencing 
Study in IPF; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $1,000,000; 
Grantee organization: 
University of Chicago: 
5801 S Ellis Ave: 
Chicago, IL 60637; 
Grant category: New applications; 
Abstract description: Idiopathic Pulmonary fibrosis (IPF) is a 
progressive untreatable lung disease. IPF has eluded causal genetic 
determinants that may provide targets for novel therapeutic 
approaches. The objective of this proposed research is to identify 
causal genetic variants contributing to risk of IPF using a Genome-
wide association studies (GWAS) panel in a large complied cohort. Each 
DNA sample is accompanied by detailed phenotypic data. To meet this 
objective we have the following specific aims: Specific Aim 1. To 
establish a combined cohort of over 700 IPF patients and perform a 
Genome Wide Association Study (GWAS) in 450 subjects with IPF. The 
hypothesis to be tested is that inheritable genetic factors affect 
individual susceptibility of IPF. To accomplish this we will establish 
clinically meaningful definitions for disease phenotypes in a merged 
manually and electronically curated database of all 700 collaborator 
patient sample sets of IPF patients and then perform a complete a GWAS 
using Affymetrix SNP 6.0 GeneChip(R) in 450 IPF patients and deposit 
the GWAS genotype and phenotype data in the NIH repository in dbGap. 
Specific Aim 2. Conduct both standard and novel analyses in genetic 
variation by phenotypes severity and rapidity of progression. The 
hypothesis to be tested is that inheritable genetic factors influence 
prognosis and severity of the disease. To accomplish this we will 
determine SNPs associated with IPF utilizing publicly deposited 
genotyped control GWAS data and evaluate copy number polymorphisms via 
available probes, and test for association with IPF phenotypes and 
determine if the associated variants differ in frequency between 
subjects with "rapidly progressive" IPF with high mortality versus 
those with "slow" IPF, severity grade or other clinical outcome 
measures Specific Aim 3. Perform Exon-Wide targeted DNA sequencing and 
genotyping to validate the GWAS associated genetic variants and to 
discover functional variations in Caucasians and African Americans 
with IPF. The hypothesis to be tested is that Exon-Wide sequencing of 
subjects with different ethnic and racial backgrounds and severity 
cohorts will allow the identification of causal/functional variants 
associated with IPF. We will replicate the most significant 
associations with a selective SNP array in a replicate IPF patient 
cohort of 200 subjects and then perform Exon-wide sequencing of 48 
genes in 160 Caucasian and African American subjects using Illumina 
454 technology and conduct a statistical analysis of exon variants 
discovered in sub-aim b. We expect that completion of a genome-wide 
association study using clinically meaningful phenotypes coupled to 
exon-wide re-sequencing will lead to identification of the genes and 
the specific genetic variants that contribute to the development of 
IPF. This can then be used as guide to lead to new approaches for 
preventing and treating this deadly disease. 

Grant project title 20: New Faculty Recruitment to Enhance Resources 
in Hypertension Research; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $1,300,399; 
Grantee organization: 
Tulane University Of Louisiana: 
6823 St Charles Ave: 
New Orleans, LA 70118; 
Grant category: New applications; 
Abstract description: The mission of the Tulane Hypertension and Renal 
Center of Excellence (THRCE) is to stimulate research activities 
related to cardiovascular, kidney, and hypertension related diseases 
and is a multidisciplinary Center with members from clinical and basic 
science departments. This application proposes to augment and expand 
biomedical research efforts in the area of cardiovascular and 
hypertension related diseases by hiring one newly independent 
investigator (Nil) and providing a start-up package and all resources 
and support needed for the Nil to develop a competitive research 
program. We propose to appoint Romer A. Gonzalez-Villalobos, MD, PhD, 
a postdoctoral fellow, as a tenure track assistant professor in the 
Department of Physiology. With this plan, the center seeks to provide 
the new faculty with an enriched environment, and enhance the center's 
research resources by creating a new core for cardiovascular and renal 
mouse phenotyping. In this regard Dr. Gonzalez is uniquely qualified 
to perform phenotyping studies in mice by virtue of his academic 
background, experience and technical training. For the pilot project 
Dr. Gonzalez-Villalobos has formulated the hypothesis that during Ang 
ll-induced hypertension, intrarenal ACE-derived Ang II formation is 
required in order to augment Ang II levels in the kidney that in turn 
increase sodium and water retention, increase miR-21 expression, and 
lead to the progressive development of high blood pressure and renal 
injury. Experiments will be performed in tissue-specific ACE knockout 
mice in order to address this hypothesis. The plan for fostering and 
monitoring the NIl includes providing the candidate with the requisite 
infrastructure, equipment and technical support; establishing an 
atmosphere conducive to a strong collaborative network; providing a 
forum for critical evaluation of experimental design, results, papers 
and grant proposals; and encouraging the candidate's attendance and 
participation in national and international meetings as well as 
involvement in scientific societies and active pursuit of funding. The 
proposed plan will provide the means to develop and support the new 
faculty in his quest to improve our understanding of the mechanisms 
participating in angiotensin II synthesis in the kidneys and its role 
in the development of hypertension. This is important because 
angiotensin II is a hormone that plays a major role in the control of 
renal function, the development of hypertension and kidney damage. 

Grant project title 21: Advancing Physical Activity Measurement Using 
Pattern Recognition Techniques; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $985,004; 
Grantee organization: 
University of Massachusetts Amherst: 
70 Butterfield Terrace: 
Amherst, MA 01003-9242: 
Grant category: New applications; 
Abstract description: In October, 2008 the US Department of Health and 
Human Services issued the first-ever federally mandated Physical 
Activity Guidelines for Americans. The Guidelines reflect the view of 
the Physical Activity Guidelines Advisory Committee (PAGAC) and are 
based on an extensive review of the scientific literature on physical 
activity (PA) and health. In their report, the PAGAC points out the 
limited knowledge of the dose-response relationship between PA and 
health, and identifies poor measures of PA exposure as a major 
contributing factor to this gap in knowledge. Our application directly 
addresses this issue by applying innovative technologies to measure PA 
dose in a free-living environment. We will use these technologies to 
examine if habitual PA performed outside of purposeful exercise 
influences biomarkers of cardiovascular health. Although insufficient 
PA clearly correlates with an increased risk for cardiovascular 
disease (CVD), research evidence is equivocal regarding the effects of 
training on CVD risk factors (e.g. insulin action, triglycerides, 
blood pressure, and cholesterol). Research suggests increases in 
sedentary behavior may negate the benefits of training however this 
idea has not been explored experimentally. Our application will 
consider habitual free-living PA as a possible mechanism mediating the 
relationship between training and risk factors for cardiovascular 
disease. In order to elucidate the relationship between PA and 
biomarkers of cardiovascular disease risk, it is critical that valid, 
objective measures are used to quantify PA. We propose to use novel 
analytic techniques known as artificial neural networks (ANN) to 
process accelerometer-based measurements of PA. The first part of this 
project (Aim 1) will examine the ANN's sensitivity to change in PA 
dose by applying the ANN technique to distinguish three distinct 
patterns of habitual PA - Sedentary, Moderately Active, and Very 
Active. These three conditions represent common activity patterns that 
impact health. Accurately assessing changes to habitual PA levels that 
are relevant to public health will advance the field by further 
establishing a technique for application in population surveillance 
research and detection of changes in PA consequent to an intervention. 
The second part of this project (Aim 2) will apply the ANN methodology 
to examine the effect of free-living activity and inactivity levels, 
performed outside of training, on insulin action, blood pressure, 
triglycerides, cholesterol, and cardiorespiratory fitness following a 
12-week exercise training trial in previously sedentary individuals 
with an elevated risk for CVD. Results from this study have the 
potential to impact how clinical exercise trials are conducted (e.g. 
require objective monitoring of PA outside of an exercise training 
trial) and how exercise is prescribed (e.g. reducing sedentary time 
AND maintaining sufficient PA). The Physical Activity Guidelines 
Advisory Committee advocates improved measures of physical activity 
exposure in order to elucidate the relationship between physical 
activity dose and health. To address this challenge we will apply and 
validate innovative accelerometer-based technologies for measuring 
physical activity to assess its sensitivity to detecting changes in 
dose of physical activity and to monitor activity outside of a 
training program designed to improve cardiorespiratory fitness and 
biomarkers of cardiovascular disease risk. Through improved measures 
of physical activity this project will promote a better understanding 
of how the dose of physical activity affects selected health outcomes. 

Grant project title 22: ECG-derived cardiopulmonary coupling 
biomarkers of sleep, sleep-breathing, and ca; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $1,000,000; 
Grantee organization: 
Beth Israel Deaconess Medical Center: 
Boston, MA 02215: 
Grant category: New applications; 
Abstract description: The traditional approach to quantifying sleep 
and sleep-respiration relies on manual or computer assisted scoring of 
30 second epochs, tagging of discrete fast phasic 
electroencephalographic events as arousals, and thresholds to identify 
pathological breathing. The scoring rules are usually reliant on a 
single physiological stream to make a determination, such as arousals 
from the electroencephalogram. However, arousing stimuli reliably 
induce simultaneous transient changes in numerous physiological systems 
- electrocortical, respiratory, autonomic, hemodynamic, and motor. 
These multiple linked physiological systems seem to show important 
patterns of coupled activity that current staging/scoring systems do 
not recognize. The respiratory chemoreflexes track oxygen (O2) and 
carbon dioxide (CO2) levels in the blood. Disease states can alter the 
set-point or response slope of the respiratory chemoreflexes, such 
that they are less (e.g., obesity hypoventilation syndrome) or more 
(e.g., central sleep apnea) sensitive to O2 and CO2 fluctuations. An 
ability to quantify and track the respiratory chemoreflexes during 
sleep could have clinical use, as (1) In certain conditions like 
congestive heart failure, chemoreflex sensitivity is reliably 
increased, correlates with disease severity and outcomes, and 
contributes to the high prevalence of sleep-disordered breathing. (2) 
Heightened respiratory chemoreflexes may contribute to obstructive 
sleep apnea severity, be associated with induction of central apneas 
when continuous positive airway pressure (CPAP) is used for treatment, 
and possibly impair long term efficacy and tolerance. Patients with 
obstructive sleep apnea who fail CPAP therapy due to induction of 
central apneas and periodic breathing (called "complex sleep apnea") 
are not otherwise distinguishable from CPAP-responsive patients. A 
biomarker that can track chemoreflex modulation of sleep respiration 
will provide a new view of short and long-term dynamic sleep 
physiology with important clinical implications. The approach proposed 
here is to analyze coupled sleep oscillations to mathematically 
extract state characteristics and modulatory influences. The 
fundamental idea is that mapping common themes encoded within multiple 
(2 or more) physiologically distinct but biologically linked signal 
streams (such as electrocortical, autonomic, respiratory and motor) 
yields evidence of deeper regulatory processes not evident by the 
current approach of scoring /staging sleep with electroencephalogram 
or airflow patterns alone. We have developed a method that needs only 
a single channel electrocardiogram (ECG), is automated, can have 
parametrically varied detection thresholds, and is readily repeatable. 
From the ECG, we extract heart rate variability (HRV) and ECG Rwave 
amplitude fluctuations associated with respiratory tidal volume 
changes (the ECG-derived respiration, EDR). The next step is to 
mathematically combine the HRV and EDR to generate the cross-product 
coherence of cardiopulmonary coupling, which yields the sleep 
spectrogram. The sleep spectrogram shows high (0.1-1 Hz, low (0.1-
0.01) and very low (0.01-0 Hz) coupling spectra that show spontaneous 
shifts between states in health and disease. High frequency coupling 
(HFC) is the biomarker of stable and physiologically restful sleep, 
low frequency coupling (LFC) is unstable or physiologically aroused 
sleep, and very low frequency coupling (VLFC) is wake or REM sleep. 
Health is dominated by HFC, diseases such as sleep apnea by LFC. A 
subset of LFC that correlate with apneas and hypopneas is elevated LFC 
(e-LFC). The stronger the chemoreflex modulatory influence on e-LFC, 
the more likely the coupling spectral dispersion narrows, yielding 
narrow band e-LFC (i.e., metronomic oscillations with a relatively 
fixed frequency). Narrow band e-LFC is induced by high altitude, heart 
failure, and predicts central apnea induction during positive pressure 
titration. The development and progression of heart failure is 
associated with fragmented sleep and heightened chemoreflex 
sensitivity. We predict that HFC will decrease and narrow band e-LFC 
will emerge and increase with worsening heart failure. These spectral 
biomarkers should change dynamically with heart failure progression or 
regression - viewing cardiac function through the window of sleep. Our 
experiments will take the following approach. We will establish the 
hemodynamic correlates of spectrographic stable and unstable sleep and 
night-to-night stability/variability of the ECG-derived biomarkers in 
adults and children in health, and in those with sleep apnea. Next, we 
will use a model of altitude-induced periodic breathing, which is 
relatively pure chemoreflex-mediated sleep apnea, to adjust the 
spectrogram's parameters that allow the best sensitivity and 
specificity for detecting chemoreflex influences on sleep respiration. 
We will in parallel track the progress of heart failure patients from 
a hospitalization episode for 6 months, attempting to show that 
reductions of HFC and emergence or increases in narrow band e-LFC are 
sentinel biomarker events that predict worsening of heart failure (an 
early warning system). Finally, we will assess clinical outcomes based 
on spectral phenotyping of an archived data set, the Apnea Positive 
Pressure Long-term Efficacy Study. In the 2-year duration of the 
award, we will validate a unique biomarker of sleep, sleep-breathing, 
and cardiovascular biology that can be applied immediately to improve 
health outcomes. 

Grant project title 23: Development of a Cardiovascular Surveillance 
System in the CVRN; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $7,217,106; 
Grantee organization: 
Kaiser Foundation Research Institute: 
Oakland, CA 94612: 
Grant category: New applications; 
Abstract description: This project will establish a surveillance 
system for cardiovascular disease in approximately 11 million health 
maintenance organization (HMO) members. The surveillance system will 
be initially established for coronary heart disease (CHD), heart 
failure (HF), and stroke. The broad goals of this project are to: 1. 
Establish a surveillance system for coronary heart disease (CHD), 
heart failure (HF) and stroke in the 15 centers of the National Heart 
Lung and Blood Institute (NHLBI) funded Cardiovascular Disease 
Research Network including therapeutic interventions, post-event 
outcomes and important risk factors and confounders. 2. Work 
collaboratively to establish and implement an aggregate database 
incorporating coronary heart disease CHD, HF, and stroke data from all 
15 CVRN sites that can be used by CVRN investigators and other 
qualified research scientists to conduct studies related to 
comparative effectiveness and health disparities. 3. Identify standard 
criteria for coronary heart disease, heart failure and stroke clinical 
outcomes, as well as all components noted in goal #1 to enable data 
aggregation 4. Determine the most recent 10-year trends in the rates 
of acute myocardial infarction and stroke hospitalization and their 
relationship to trends in risk factors, co-morbidities, therapeutic 
interventions, medications, and diagnostic modalities. 5. Demonstrate 
that the data can be used to address research questions regarding 
comparative effectiveness and novel methods of monitoring health 
disparities, areas that have been identified as RC2 topics by NHLBI. 
This project will result in a surveillance system in a consortium of 
15 geographically diverse health plans that provide health care to 
about 11 million people, nearly 4% of the U.S. population. This 
surveillance system will be significantly larger than other existing 
cardiovascular surveillance efforts in the U.S. and includes a 
population that is diverse in race/ethnicity and sociodemographic 
characteristics. The surveillance system will include for CHD, HF, and 
stroke electronically available data on risk factors, co-morbidities, 
prescription medications, therapeutic interventions, and laboratory 
testing, and physician and patient characteristics. These data can be 
utilized to provide timely surveillance reports for CHD, CF, and 
stroke; a comprehensive description of a patient's longitudinal course 
both prior to and subsequent to development of CHD, CF, and stroke; 
and enable research questions to be addressed that assess the 
relationship of these variables to the course of disease as well as to 
address research questions relating to comparative effectiveness and 
to disparities in medical treatment and outcomes. 

Grant project title 24: Novel Imaging to Predict Cardiovascular Events 
in Diabetes; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $1,625,296; 
Grantee organization: 
Mount Sinai School of Medicine of NYU: 
New York, NY 10029-6574: 
Grant category: Existing applications; 
Abstract description: Novel non-invasive imaging tests have been 
developed to characterize atherosclerotic plaque burden and metabolic 
activity (inflammation). However, the value of these atherosclerosis 
imaging technologies for predicting coronary heart disease (CHD) and 
stroke events has not been evaluated in prospective studies. Proposed 
is a study to conduct noninvasive imaging and longitudinal follow-up 
in a high risk cohort of patients with diabetes by utilizing the 
recruitment network, events follow-up protocol and adjudication 
committee assembled by the NHLBI-sponsored FREEDOM Trial (Future 
REvascularization Evaluation in patients with Diabetes mellitus: 
Optimal management of Multivessel disease - HL071988). Specific aims 
of our study are (1) to determine the association of atherosclerotic 
plaque burden and the risk of CHD and stroke events and all cause- 
mortality; (2) to determine the association between traditional CHD 
risk factors and atherosclerotic plaque burden; and (3) to determine 
the association between plaque burden and plaque inflammation. In 
order to accomplish these aims, we will recruit 380 diabetic patients 
with multi-vessel coronary disease from eleven greater New York 
metropolitan area hospitals. Patients will complete a baseline study 
visit at Mount Sinai School of Medicine (MSSM) to assess plaque burden 
and plaque inflammation by magnetic resonance (MR) (contrast and non 
contrast) and fluorodeoxyglucose (FDG)-positron emission tomography 
(PET) imaging. Additionally, questionnaires will be administered, a 
physical examination conducted and blood specimens collected to 
measure hemostatic and inflammatory markers. Patients will be actively 
followed for 36 months through annual inperson study visits and bi-
annual telephone follow-up. When events (mortality, non-fatal MI and 
non-fatal stroke) are identified, hospital charts and death 
certificates will be reviewed by an adjudications committee, blinded 
to the baseline measurement values. Changes in plaque burden and 
inflammation will be assessed through MR and FDG-PET imaging, 
respectively, at the 36 month follow-up visit again at MSSM. The 
proposed study will provide the unique opportunity to assess 
atherosclerotic plaque burden as a predictor for clinical events in a 
high risk patient cohort. Data from this study will not only advance 
our understanding of the aggressive atherosclerotic process associated 
with diabetes but will also provide us with a strategy to combine 
novel noninvasive approaches to better follow the effects of medical 
and revascularization therapy in the diabetic patient. It is our 
expectation that data from the proposed study will be utilized to 
evaluate and improve existing treatment and help guide the development 
of effective new therapies aimed at reducing CHD and stroke events and 
improving survival in high risk diabetic patients. 

Grant project title 25: Pneumocystis jirovecii and macrophages in COPD; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $148,416; 
Grantee organization: 
University of Kentucky: 
109 Kinkead Hall: 
Lexington, KY 40506-0057: 
Grant category: Existing applications; 
Abstract description: Airway inflammation, airway remodeling, 
colonization with microorganisms, and parenchymal destruction are 
hallmarks of chronic obstructive pulmonary disease (COPD). In addition 
to cigarette smoking, infectious pathogens likely contribute to the 
decline in pulmonary function in COPD patients. The inflammatory 
process in patients with COPD displays a distinct pattern of 
inflammatory mediators and immune cells that are involved that are 
similar to the pattern seen in response to Pneumocystis jiroveci (PC). 
Evidence has now emerged on the importance of macrophage phenotype in 
COPD patients. Macrophages account for the majority of inflammatory 
cells recovered from bronchoalveolar lavage from COPD patients and are 
localized to sites of alveolar destruction. Further, the IL-4/IL-13 
alternatively activated macrophage phenotype (AAM) has been implicated 
in several chronic lung diseases. We propose in this study to evaluate 
the relationship between the AAM and PC in lungs of COPD patients in 
the Lung Tissue Research Consortium. In 3 Aims we will (1) correlate 
PC colonization with the presence of AAMs in lung tissue samples, (2) 
determine through immunohistochemistry how the presence of PC 
correlates to the precise localization of macrophage phenotype and 
fibrosis, and (3) determine how PC burden and AAMs correlate to 
clinical outcome measurements. This project will investigate a novel 
mechanism of pathogenesis which may provide targets for potential 
future therapeutic interventions for patients with COPD. 

Grant project title 26: Pathological Consequences of the Plasminogen 
System; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $750,000; 
Grantee organization: 
University of Notre Dame: 
940 Grace Hall: 
Notre Dame, IN 46556: 
Grant category: Existing applications; 
Abstract description: The long-term goal of this proposal is to 
identify functions and determine mechanisms of the fibrinolytic 
system, and its inhibitors, in physiological and pathological 
processes utilizing cell-based and in vivo models. The availability of 
mice with deficiencies of genes of the fibrinolytic system has 
resulted in direct analyses of the role of these proteins in a number 
of biological events. Studies have indicated that a PAI-1 deficiency 
diminishes angiogenesis in tumor models. Further, our laboratory has 
shown that endothelial cell (EC) signaling and function are regulated 
by PAI-1/LRP interactions. The current application will further 
elucidate effects of PAI-1 on cell signaling pathways and determine 
the importance of PAI-1/LRP interactions in both cellular and 
physiological events. As a result of these observations, the following 
studies are proposed: (1) Determine the effects of a PAI-1 deficiency 
on murine EC JAK/STAT signaling and cell cycle progression. These 
studies will assess STAT and JAK expression profiles and activation 
status in proliferating wild-type (WT) and PAI-1-/-EC as well as the 
extent of nuclear translocation of STAT. The addition of rPAI-1 and 
mutants will determine which functional domains of PAI-1 regulate the 
activation status of this pathway. Additional studies will determine 
effects on cell migration. Downstream effects on cell cycle 
progression will also be investigated. The hypothesis is that a PAI-1 
deficiency will affect JAK/STAT signaling and downstream cell cycle 
progression, and that these effects are mediated by PAI-1/LRP 
interactions. (2) Characterize early and late stage events of cardiac 
fibrosis in PAI-1-/-and uPA-/-/ PAI-1-/-mice. Recent studies have 
shown that PAI-1-/-mice develop cardiac fibrosis, which may be 
mediated by dysregulated uPA or chronic activation of the Akt pathway, 
the result of altered PAI-1/LRP interactions. The studies proposed 
will initially characterize cardiac fibrosis in PAI-1-/-and uPA-/-/PAI-
1-/-mice in order to differentiate effects from uPA activity and PAI-1 
functions independent of uPA inhibition in cardiac fibrosis 
phenotypes. The hypothesis is that cardiac fibrosis will be regulated 
by urokinase activity and other functions of PAI-I which will be 
further pursued in future studies of mice expressing functional 
mutations of PAI-1. 

Grant project title 27: Pilot Test of a Novel Behavioral Intervention 
on BP Control in HTN Patients; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $1,506,522; 
Grantee organization: 
Pennsylvania State University-Univ Park: 
110 Technology Center Building: 
University Park, PA 16802; 
Grant category: Existing applications; 
Abstract description: Patients' knowledge concerning their chronic 
illness has long been considered "necessary but not sufficient" to 
produce changes in risk-related behaviors. "Necessary" implies that 
patient knowledge is, therefore, a moderator of the effectiveness of 
behavioral interventions. However, researchers have tended to ignore 
patient education as a critical component of behavioral (or, for that 
matter, pharmacological) interventions. We propose to combine a 
behavioral intervention that we and others have found to be moderately 
effective in increasing blood pressure (BP) control in hypertensive 
patients - using a home BP monitor (HBPM) to obtain feedback regarding 
their BP control, and providing feedback to the health provider - with 
a systematic patient education component. We propose an intervention 
strategy that is meant to be usable as an adjunct to the HBPM and 
other interventions; one that will increase patients' knowledge, and, 
we hypothesize, will therefore increase the effectiveness of the 
"parent" intervention (HBPM, in this case). Our proposal is for a 
randomized controlled trial (RCT), using a 2X2 factorial design in 
which we will test the effect of (1) a patient education intervention 
and (2) HBPM, on ambulatory BP in poorly-controlled hypertensive 
patients at 3 and 6 months. The education intervention is based on a 
technique called "Self-Paced Programmed Instruction" (SPPI), a method 
that has been remarkably effective at increasing knowledge concerning 
complex topics. Using a computer, a paragraph of content material is 
presented, followed by probe questions. When patients provide a 
correct response, they are immediately reinforced by positive 
feedback; an incorrect response loops the program to represent the 
materials, this time with hints; and the subjects then re-attempt the 
probe questions. The loop continues until a correct answer is 
recorded. In this manner, every subject achieves mastery over the 
requisite material. We posit that medication adherence (assessed 
objectively) will partially mediate the ambulatory BP outcomes; and 
that Self-Efficacy for the self-management of HTN will mediate 
medication adherence; we predict that self-efficacy will be enhanced 
by the mastery of the HTN-related materials, and by the reduction of 
ambiguity, which will lead to greater confidence in the patient's 
decision-making processes. We predict that the SPPI - HBPM condition 
will have the greatest effect on ambulatory BP, compared to the other 
three groups. 

Grant project title 28: CRP, Diabetes, Atherothrombosis; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $908,083; 
Grantee organization: 
University of California Davis: 
Office of Research - Sponsored Programs: 
Davis, CA 95618: 
Grant category: Existing applications; 
Abstract description: In the previous proposal, the central hypothesis 
was to determine if CRP promotes atherothrombosis by effects on both 
endothelial cells and monocytes. We have now executed all four aims of 
this proposal and have advanced the field with regards to the vascular 
effects of CRP. In summary, we have elucidated the molecular mechanism 
by which CRP inhibits eNOS (in-vitro and in-vivo), we have documented 
the role of Fc-gamma receptors in the biological effects of CRP on 
endothelial cells, macrophages and in Wistar rats. Furthermore, we 
have elucidated the mechanism of CRPinduced monocyte adhesion under 
shear stress, and finally we have confirmed in-vivo, in Wistar rats, 
that CRP has effects that promote atherosclerosis including 
stimulation of NADPH-oxidase, superoxide, MPO release, oxidized LDL 
uptake, tissue factor, MMP-9 release from macrophages and decreased 
vasoreactivity. Diabetes is a proinflammatory state that is 
characterized by high CRP levels. However, there is a paucity of data 
examining the role of CRP in promoting the pro-inflammatory state in 
diabetes. We have shown in exciting and novel preliminary data that 
CRP exacerbates in-vivo the pro-inflammatory, pro-oxidant effects in 
the diabetic milieu (spontaneously diabetic BB rat). Thus, in this 
competing renewal, we wish to further explore the effects of CRP on 
diabetes and atherothrombosis. To this end, we are proposing two 
specific aims. In specific aim 1, we will continue to expand our 
exciting preliminary findings that CRP accentuates the pro-
inflammatory, pro-oxidant state in the diabetic BB rat. In this model, 
we will confirm if CRP exacerbates in-vivo the pro-inflammatory, pro-
oxidant effects in the diabetic milieu and also elucidate the 
molecular mechanism (s) by which CRP exerts these effects by employing 
in-vivo siRNA and antisense oligonucleotides to the different pathways 
identified. Based on findings largely from our group and others, that 
CRP promotes a pro-coagulant phenotype, in Specific Aim 2, using the 
spontaneously diabetic BB rat, we will now test in-vivo the effect of 
CRP on thrombosis in the diabetic milieu. Also, we will elucidate the 
mechanism (s) by which CRP promotes atherothrombosis in the diabetic 
state. We believe these studies will provide further novel data in 
support of the hypothesis that CRP promotes atherothrombosis in-vivo 
and a procoagulant, pro-inflammatory phenotype in diabetes. Probing 
into the molecular mechanisms by which CRP augments oxidative stress 
and inflammation in the diabetic milieu will eventually lead to 
therapies targeted at reducing inflammation and oxidative stress in 
diabetes and resulting in a decrease in vasculopathies. 

Grant project title 29: Genetic control of gene expression during 
innate immune activation; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $249,216; 
Grantee organization: 
University of Washington: 
Office of Sponsored Programs: 
Seattle, WA 98195-9472; 
Grant category: Supplements and revisions; 
Abstract description: Innate immune responses are induced by specific 
interactions between pathogen-associated molecules and Toll-like 
receptors (TLRs), and are critical to host defense. Recent studies 
have shown a role for TLR7 and TLRS in innate immune responses to 
viral infection. However, it is unknown to what extent these innate 
immune responses are heritable and what loci might affect this 
heritability. Our overall hypothesis is that heritable variation 
exists in gene expression levels measured during an innate immune 
response to virus-associated molecules. We propose to study this 
hypothesis in the context of innate immune responses to synthetic 
agonists specific for TLR7 (imiquimod) or both TLR7 and TLR8 (R848). 
First, we will determine genome-wide heritability of R848-induced 
changes in gene expression using a classical twins study. We will then 
identify quantitative trait loci (QTL) that control heritable 
variation in TLR7-induced gene expression in B-lymphoblastoid cell 
lines (B-LCL) isolated from 'HapMap' trios, and we will fine-map the 
functional polymorphisms within these QTL in a large cohort of healthy 
individuals. Finally, we will apply in vitro assays of promoter 
function and RNA processing to understand how these polymorphisms 
affect gene expression. The proposed studies will identify specific 
genetic loci controlling heritability of TLR7/8-mediated innate immune 
responses and more broadly, basic mechanisms underlying the genetic 
control of gene expression in environmentally perturbed cells. Results 
from these studies will provide novel potential markers of 
susceptibility for both common and emerging viral infection and will 
characterize a new experimental pathway for discovery of functional 
genetic variation affecting responses to environmental stimuli. 

Grant project title 30: Negative regulation of platelet activity; 
Administering IC: National Heart, Lung and Blood Institute; 
Grant award size: $260,197; 
Grantee organization: 
Bloodcenter of Wisconsin, Inc. 
P.O. Box 2178: 
638 N 18th St: 
Milwaukee, WI 53233; 
Grant category: Supplements and revisions; 
Abstract description: Platelets are anucleate bodies that circulate in 
the bloodstream and play a very important role in vascular hemostasis. 
Platelets circulate in a quiescent state in intact blood vessels but 
they adhere to and become activated by exposed extracellular matrix in 
a damaged vessel. Activated platelets spread out and bind to one 
another (i.e., form a thrombus), so as to close up the damaged area 
and initiate wound healing. Excessive bleeding occurs when platelets 
are deficient or hypo-responsive and pathological thrombus formation, 
which can result in occlusion of blood vessels and cause myocardial 
infarction or stroke, occurs when platelets are hyper-reactive. 
Because the extent of platelet activation is such an important 
determinant of vascular pathology, it is very important to understand 
how platelet activation and aggregation are regulated. The platelet 
contains several cell surface and intracellular proteins that 
coordinate transmission of activating and inhibitory signals into the 
platelet interior, and it is the balance of stimulatory and inhibitory 
cues that ultimately determines the platelet activation state. Whereas 
much has been learned in recent years regarding the platelet receptors 
and signaling cascades that contribute to platelet activation, key 
components of which are members of the Src Family of protein tyrosine 
Kinases (SFK), the molecules and pathways responsible for keeping 
platelet activation held in check remain poorly defined. We and others 
have previously demonstrated that Platelet Endothelial Cell Adhesion 
Molecule-1 (PECAM-1, also called CD31) and the SFK, Lyn, are negative 
regulators of platelet activation. Previous studies in our laboratory 
have also begun to characterize, in platelets, a pathway by which C- 
terminal Src kinase (Csk) is recruited to sites of SFK activity by Csk 
Binding Proteins (CBP), so that Csk may carry out its important role 
as a negative regulator of SFK activity. In particular, our 
preliminary studies have revealed that a member of the Downstream of 
kinase (Dok) family, Dok-2, is a CBP in platelets. The overall goal of 
this new grant application is to develop a more complete list of 
inhibitory molecules in platelets, to thoroughly characterize the 
signaling pathways in which these molecules function, and to improve 
our understanding of how these molecules and pathways interact with 
one another to ultimately influence the platelet activation state. 
Specifically, over the next three-year period, we propose to: (1) 
determine the contribution of the inhibitory SFK, Lyn, to the 
inhibitory function of PECAM-1 and (2) determine how Csk binding to 
Dok-2 contributes to negative regulation of platelet activation. 
Together, these studies comprise a coordinated, focused research 
program designed to improve our understanding of negative regulation 
of platelet activation by identifying, characterizing, and examining 
the interactions between inhibitory receptors and signaling molecules 
in platelets, such as PECAM-1, Lyn, and Dok-2. We expect that 
information derived from this investigation has the potential to lead 
to improved diagnosis and treatment of bleeding disorders, myocardial 
infarction and stroke. 

Grant project title 31: Amplification of Antiviral Innate Immunity by 
Suppressor of Virus RNA (svRNA); 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $999,998; 
Grantee organization: 
Cleveland Clinic Lerner COL/MED-CWRU JJN5-01: 
Cleveland, OH 44195: 
Grant category: New applications; 
Abstract description: RNA cleavage is a fundamental and ancient host 
response for controlling viral infections in both plants and animals. 
In higher vertebrates, including humans, RNA cleavage as a means of 
controlling viruses is mediated by the type I interferons (IFN) 
through its effector, the uniquely regulated endoribonuclease, RNase 
L. RNase L is activated by unusual 2',5'-linked oligoadenylates (2-5A) 
produced during viral infections. 2-5A activates RNase L resulting in 
cleavage of host and viral RNAs within single stranded regions, 
predominantly after UU and UA. As a result of its specificity, RNase L 
produces small, highly structured RNA cleavage products. In 2007 we 
reported that RNA cleavage products obtained from digestion of self 
RNA by RNase L activated RIG-I-like receptors (RLR) resulting in 
amplification of type I IFN synthesis. These RNA cleavage products 
represent a novel class of small RNA molecules named "Suppressor of 
Virus RNA" (svRNA). Our GOALS in this project are to clone, identify 
and probe the functions of svRNAs generated from both host RNA and 
from viral [hepatitis C virus (HCV)] RNA. Our HYPOTHESIS is that 
svRNAs are essential to host defense against a wide range of viruses 
that are pathogenic for humans. Our Specific Aims are: (1) to isolate 
and identify svRNA liberated by RNase L from host and viral RNA, we 
will cleave HCV RNA with purified RNase L and clone small RNAs that 
bind to RLRs, and cleave cellular (self) RNA in intact cells treated 
with 2-5A and clone small RNAs that bind to RLRs; (2) To characterize 
activation of RIG-I and MDA5 by svRNAs we will perform ATPase 
activation studies, determine the kinetic parameters for svRNA 
interactions with RIG-I and MDA5 by surface plasmon resonance, measure 
conformational changes in RIG-I and MDA5, and establish the sequence 
and structural requirement of svRNA for activation of RIG-I and MDA5; 
and (3) to determine the role of svRNA in antiviral innate immunity we 
will identify svRNAs in HCV infected cells, and determine the 
antiviral effects of svRNAs in mice. Our recent studies suggest an 
essential role of svRNAs in the antiviral state in higher vertebrates. 
In the proposed studies we seek to obtain a fundamental understanding 
of this important pathway as it relates to host defense against 
viruses. Therefore, there are cogent and health-related justifications 
for these studies. 

Grant project title 32: Interconnectivity between genome packaging and 
other viral functions; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $415,250; 
Grantee organization: 
University of California Riverside: 
900 University Ave: 
Riverside, CA 92521; 
Grant category: Existing applications; 
Abstract description: Information gleaned from recent studies with 
single-stranded, positive-sense RNA viruses pathogenic to humans and 
animals (polio and alphaviruses) and insects (flock house virus; FHV) 
revealed that the mechanism of genome packaging in these viral systems 
is functionally coupled to replication. Recently our laboratory 
adopted a novel in vivo system referred to as Agrobacterium-mediated 
transient expression (agroinfiltration) to study encapsidation in 
plants. This system not only allowed efficient expression of viral 
genome components either autonomously or synchronously in plant cells, 
but also effectively uncoupled replication from packaging. Application 
of the agroinfiltration system to brome mosaic virus (BMV, a plant 
infecting RNA virus) allowed us to hypothesize that packaging in BMV 
is also functionally coupled to replication. In addition, co-
expression of BMV and FHV in plant cells using agroinfiltration 
revealed that for specific RNA packaging to occur, synchronization of 
replication and transcription of coat protein (CP) mRNAs from 
homologous replication machinery is obligatory. This two-year 
exploratory project is designed to evaluate, at the sub-cellular 
level, the intimacy of replication to packaging. An agroinfiltration 
system competent to synchronously infect the same plant cell with BMV 
and FHV will be used through out these studies. Our working hypothesis 
is that translation of CP followed by virus assembly occurs very close 
to the sites of viral replication. Thus in Aim 1, we propose to 
temporally and sequentially localize and identify the sub-cellular 
compartment(s) where translation of CP and virus assembly of BMV and 
FHV occurs. In addition to the molecular and biochemical 
characterization, delineation of CP translation and virus assembly 
sites at the sub-cellular level will be investigated by electron 
microscopy using a novel Silver Enhancement-Controlled Sequential 
Immunogold technique (SECSI). BMV and FHV differentially replicate on 
the outer membranes of endoplasmic reticulum (ER) and mitochondria 
respectively. We found that packaging is non-specific when BMV CP or 
FHV CP was expressed either transiently or via heterologous 
replication. Thus, experiments outlined in Aim 2 are focused in 
addressing, for the packaging specificity occur, whether viral progeny 
RNA need to be tethered to the same membrane near which it's CP is 
being actively synthesized. This will be investigated by retargeting 
the FHV replicase complex to the ER, where the synthesis of FHV CP 
from genetically engineered BMV RNA will be synchronized. At the 
completion of the project we should know whether translation of CP and 
assembly of virions occur at or near the replication sites and whether 
tethering of viral progeny RNA to the same membrane near which it's CP 
is being actively synthesized is obligatory to confer packaging 
specificity. Results obtained from this research proposal would 
improve our understanding concerning the mechanism of replication-
coupled packaging in RNA viruses pathogenic to humans, animals and 
plants. 

Grant project title 33: Targeting pDCs for the Generation of Effective 
Anti-HCV CD8+ T-Cell Immunity; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $429,000; 
Grantee organization: 
Baylor Research Institute: 
Dallas, TX 75204: 
Grant category: Existing applications; 
Abstract description: Hepatitis C virus (HCV) infection represents a 
significant global health-care problem, which is forecasted to become 
worse in the coming years. In the developed world, infection with HCV 
is responsible for 50-75% of all cases of liver cancer and accounts 
for two-thirds of all liver transplants. To date there are no 
effective vaccines to HCV and current systemic therapies have 
significant side effects. There is a need for novel therapeutic 
approaches to the treatment of chronic hepatitis C infection. The 
establishment of potent anti-viral CD8+ T-cell immunity has been shown 
to be the central mediator of viral clearance. Like many chronic 
infections however, such responses to HCV have been difficult to 
establish. Plasmacytoid dendritic cells (pDCs) are a subset of DCs 
which are specialized for viral recognition and the initiation of anti-
viral immunity. We have shown that pDCs have specialized antigen 
processing compartments (MICs) which permit them to rapidly cross-
present viral antigens and stimulate protective CD8+ T-cell responses. 
Furthermore we have demonstrated that targeting antigens to this 
compartment in an activated pDC is sufficient to initiate potent CD8+ 
Tcell responses. Our overall hypothesis is that Hepatitis C viral 
antigens targeted to the specialized class-I processing compartment 
(MIC) of pDCs will be efficiently cross-presented and drive anti-viral 
CD8+ T cell expansion. We propose to address this hypothesis though 
three aims; Aim 1: To determine if receptor trafficking into the MIC 
is sufficient to generate strong CD8+ T-cell responses against 
Hepatitis C viral antigens. We will address this hypothesis by (1) 
Generating antibody antigen conjugates for in vitro targeting to the 
MIC. (2) Assess the effect of these reagents on pDC activation (3) 
Demonstrate MIC targeting (4) Demonstrate cross-presentation of 
targeted antigen. Aim 2: To determine if antigen processing and cross-
presentation by the pDC results in an expanded antigen specific T-cell 
repertoire. We will (1) Demonstrate that antibody antigen conjugates 
can induce potent HCV antigen specific CD8+ T cells responses in vitro 
(2) Determine the optimal CpG derivative (CICs) to enhance viral 
antigen specific CD8+ T cell responses (3) Make both a quantitative 
and qualitative assessment of total T-cell epitopes generated during 
cross-presentation of targeted viral antigens by pDCs. (4) Assess the 
quality of viral epitope response in patients chronically infected 
with HCV. Aim 3: The generation of a multi-epitopic adjuvant-based pDC 
targeting constructs We will (1) Generate fusion proteins of anti-
BDCA2 and the immunodominant TC1 viral epitopes identified in Aim 2. 
(2) Conjugate immunostimulatory CIC sequences to this second 
generation pDC targeting construct. (3) Demonstrate that a multi-
epitopic pDC targeting constructs can induce potent HCV antigen 
specific CD8+ T cells responses in vitro in patients chronically 
infected with HCV. Overall significance: This study provides a novel 
approach for therapeutic HCV vaccine development. 

Grant project title 34: Type II secretion system of P. aeruginosa in 
acute lung infection; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $732,500; 
Grantee organization: 
University of Florida: 
219 Grinter Hall: 
Gainesville, FL 32611-5500: 
Grant category: Existing applications; 
Abstract description: Acute lung infection due to Pseudomonas 
aeruginosa is a common cause of death in hospitalized patients. This 
organism is also the major cause of death in Cystic Fibrosis. A number 
of virulence factors have been proposed to lead to these poor 
outcomes. We wish to examine the role of the toxins secreted by this 
bacterium's type II secretion system during lung infections. Research 
in this area has been inconclusive, with most recent efforts being 
focused on the role of the type III secretion system. However, using 
Toll-like-receptors 2,4 -/-mice, we demonstrate a significant role for 
the T2SS in death due to lung infections. We therefore wish to define 
how this occurs. Our aims are to identify the outer membrane protein 
pore through which toxic factors are secreted, identify the secreted 
toxic factors using an unbiased proteomics approach and examine 
whether there is an important role for this system in other virulent 
P. aeruginosa strains during lung infections. During the course of 
these studies we will also examine whether secretion can be blocked by 
antibody raised against the secretion pore. We will utilize 
conventional molecular biology techniques of mutagenesis and 
complementation as well proteomic analyses of the secreted proteins to 
ascertain whether there are unknown toxic factors that are being 
secreted or whether it is the classic virulence factors that cause 
death. These studies reexamine a critical question that has been left 
largely unanswered, and will provide valuable information on possible 
ways of preventing death cause by the toxins produced by this system. 

Grant project title 35: Broad Neutralizing Monoclonal Antibodies From 
HIV Controllers; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $850,866; 
Grantee organization: 
University of Maryland Baltimore: 
620 W Lexington St: 
4th Fl: 
Baltimore, MD 21201-1508: 
Grant category: Existing applications; 
Abstract description: The long-term goal of this project is to 
identify novel monoclonal antibodies (mAbs) that broadly recognize the 
HIV-1 envelope glycoprotein (Env) and block infection in vitro to 
guide vaccine development. This goal will be pursued in a cohort of 
HIV-1 infected individuals who control their infections in the absence 
of anti-retroviral therapy (Natural Virus Suppressors/NVS) and who 
have circulating broadly neutralizing antibodies (broad nAbs). A key 
element of our approach is the development of a new assay to census 
Env-specific memory B cell clones (BMem) that allows the rapid and 
direct cloning of full-length monoclonal antibodies (mAbs). These mAbs 
will be characterized for epitope specificity and neutralization 
breadth to create clonal profiles of the BMem that are generated 
during the control of HIV-1 infection. This information will be used 
to test the hypothesis that neutralization breadth is determined by a 
polyclonal response comprised of a mosaic of neutralizing 
specificities as opposed to a pauciclonal response comprised of one or 
a very few neutralizing specificities. Testing this hypothesis is key 
to our long-term goal of identifying novel mAbs that broadly recognize 
Env and block infection in vitro to guide vaccine development against 
HIV-1. There are two specific aims. Aim 1-To develop clonal 
specificity profiles of Env-specific BMem from NVS who have ongoing 
broadly neutralizing antibody responses-Clonal specificity profiles of 
anti-Env responses will be determined by limiting dilution analysis, 
mAb isolation, and epitope mapping to determine the relative dominance 
of BMem clones specific for different Env-epitopes. Aim-2-To compare 
neutralization breadth between plasma antibodies and mAbs representing 
a full clonal profile of BMem to determine the number of mAbs that 
must be pooled to reconstruct the neutralization breadth of the 
circulating antibody pool. This data will be used to determine the 
clonality of an ongoing broad nAb response. This aim will complete 
testing the hypothesis that neutralization breadth is determined by a 
polyclonal response comprised of a mosaic of neutralizing 
specificities as opposed to a pauciclonal response comprised of one or 
a very few neutralizing specificities. Currently there is no vaccine 
against AIDS. The work proposed in this application will investigate 
how some people control HIV-1 infection for many years without anti-
retroviral drug therapy. This information should be useful in making a 
vaccine against AIDS. 

Grant project title 36: Nonpayment for Preventable Complications: 
Impact on Hospital Practices and Health; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $447,156; 
Grantee organization: 
Harvard Pilgrim Health Care, Inc. 
Boston, MA 02215: 
Grant category: Existing applications; 
Abstract description: Financial incentives, such as pay-for- 
performance (P4P) programs, are increasingly being used to improve 
physician behavior. However, the impact of these programs on improving 
quality of care for patients have been mixed, with some studies 
showing modest gains and others reporting little to no improvement on 
quality of care measures. Furthermore, unintended consequences of P4P 
programs have been demonstrated, including larger financial rewards 
for those hospitals with higher performance at baseline and 
significant financial losses for hospitals that serve large minority 
populations. As of October 1, 2008, Medicare will implement the use of 
a new financial mechanism-nonpayment for preventable complications 
(NPPC)-which is a "stick" rather than a "carrot". Medicare will no 
longer pay hospitals for treating certain healthcare associated 
infections (HAIs) that arise in patients if they are not present on 
admission. Our proposed research is unique and timely. There are no 
data available on the impact of a NPPC policy intervention that is 
being implemented by one of the largest payers in the U.S. Despite 
lack of evidence for its efficacy, it is hoped that financial 
disincentives will motivate hospitals and providers to focus their 
efforts on reducing HAIs. While the goal is certainly worthy, the 
mechanism being used to motivate change should be rigorously evaluated 
to ensure that it achieves its intended consequences without the 
occurrence of unintended consequences. Our research will provide a 
rich understanding of the potential impact, both positive and 
negative, of NPPC on patient care and outcomes. The long-term goal of 
this proposal is to assess the overall impact NPPC on patient care and 
outcomes. In this two-phase study, we will first conduct qualitative 
interviews to identify key elements that may affect hospital practices 
and rates of HAIs. In the second phase, we will develop, pilot, and 
validate a survey instrument based on our qualitative research 
findings in order to conduct a future survey of infection 
preventionists to assess the perceived impact of NPPC on hospitals in 
the U.S. Thus, we propose the following specific aims: 1. To identify 
key factors that may affect infection prevention practices in the 
context of NPPC. 2. To develop, pilot, and validate a survey 
instrument to examine the perceived impact of NPPC on behaviors and 
practices in hospitals. 

Grant project title 37: HIV-envelope-specific CD4+ T-cell activation 
and functional potentials; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $831,350; 
Grantee organization: 
St. Jude Children's Research Hospital: 
Memphis, TN 38105: 
Grant category: Existing applications; 
Abstract description: Despite decades of research, the development of 
a successful HIV-1 vaccine has not yet been achieved. A better 
understanding of the functions of activated lymphocytes is therefore 
desired. The long-term objective of our research is to comprehend the 
full potentials of HIV-1-envelope-specific immune cells. CD4+ T-cells 
contribute to HIV-1 control by supporting antibody production by 8- 
cells and the activation/maintenance of CD8+ T-cells. However, based 
on our recent data, it appears that envelope-specific CD4+ T-cells may 
additionally contribute directly to the control of virus-infected 
cells, independent of 8-cell or CD8+ T-cell activity. The studies 
proposed here will determine how these CD4+ T-cells confer their 
'protector' effect. Specific Aim: To determine the phenotype, cytokine 
secretion capacities, and killer potentials of the HIV-1 envelope- 
specific CD4+ T-cells that protect against envelope-recombinant virus 
in the absence of 8-cell or CD8+ T-cell functions. Experiments are 
designed to fill fundamental gaps in our understanding of how virus is 
controlled by the immune system. Results from these experiments may be 
invaluable to the construction of new, successful HIV-1 vaccines 
designed to capture the full potentials of the immune response. 

Grant project title 38: HIV ENV epitope engineering; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $745,000; 
Grantee organization: 
Tulane University of Louisiana: 
6823 St Charles Ave: 
New Orleans, LA 70118: 
Grant category: Existing applications; 
Abstract description: CD4+ helper T cells specific for human 
immunodeficiency virus type 1 (HIV-1) are associated with control of 
viremia. Nevertheless, vaccines have not been effective thus far, at 
least partly because sequence variability and other structural 
features of the HIV envelope glycoprotein deflect the immune response. 
Previous studies indicate that CD4+ T-cell epitope dominance is 
controlled by antigen three-dimensional structure. Three disulfide 
bonds in the outer domain of gp120 were individually deleted in order 
to destabilize the three-dimensional structure and enhance the 
presentation of weakly immunogenic epitopes. Unexpectedly, upon 
immunization of mice, the CD4+ T-cell response was broadly reduced and 
antibody titers were sharply increased for two of the disulfide 
variants. For one variant (deletion of the 296-331 disulfide 
bracketing V3), viral neutralizing activity was increased, but 
reactivity was narrow. For another variant (deletion of the 378-445 
disulfide bracketing V4 and part of the bridging sheet), the antibody 
exhibited significant CD4-blocking activity. The changes in the immune 
response are most likely due to shifts in the pathways of antigen 
processing that result in the priming of fewer but more helpful T 
cells. In the proposed research, the disulfide variants will be 
reconstructed in the gp120 of distinct Clade B and Clade C HIV strains 
and in the gp120 of an SIV strain in order to test the generality of 
the result. Disulfide variants will be characterized by binding to 
monoclonal antibodies, circular dichroism spectroscopy with 
denaturation, limited proteolysis, deglycosylation, and isothermal 
titration calorimetry of CD4 binding. Mice will be immunized with the 
variants. CD4+ T-cell proliferative and cytokine responses will be 
mapped for individual mice and, in a novel analysis, will be 
correlated with antibody reactivity to proteins and peptides. The 
resulting epitope-specific T-B correlations will be used to identify 
cellular interactions that support antibodies directed against 
protective and unprotective epitopes. Rabbits will be immunized, and 
viral neutralization will be analyzed, with the expectation that 
antisera raised by the disulfide-deletion variants will have increased 
viral neutralization. The proposed research is unique in that it 
exploits T-B relationships in order to engineer an improved antibody 
response. 

Grant project title 39: Dissecting the origin and the function of the 
cutaneous dendritic cell network; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
rant award size: $842,635; 
Grantee organization: 
Mount Sinai School of Medicine of NYU: 
New York, NY 10029-6574: 
Grant category: Existing applications; 
Abstract description: Highly specialized professional antigen 
presenting cells are distributed throughout the skin and include 
epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs). Our 
laboratory established some unique properties of cutaneous DCs. We 
discovered that in contrast to lymphoid organ DCs, LCs fail to develop 
in mice that lack the receptor for macrophage ny stimulating factor 
(MCSFR) (Ginhoux et al. Nat immunol 2006). We established that in 
contrast to most dc populations, LCs are maintained by radioresistant 
hematopoietic precursors that have taken residence in the skin in the 
steady state (Merad et nature immunology 2002; Merad et al. Nature 
medicine 2004). We also found that a subset of dermal DCs derive from 
radioresistant precursors, while the majority derives from circulating 
radiosensitive precursors (Bogunovic et al. Jem 2006). More recently, 
we identified a novel population of dermal DCs that express the c-type 
lectin receptor langerin, thought to be a LC hallmark the skin. In 
contrast to LCs, dermal langerin+ DCs are recruited from the blood and 
sojourn briefly in the skin before migrating to the lymph node charged 
with skin antigens (Ginhoux et al. Jem 2007). These results underline 
the complexity of the cutaneous dc network system, but "the raison 
d'etre" and the mechanisms that regulate the development of this 
complex system is elusive. In this grant application, we propose to 
dissect the origin of dc populations in the skin, identify the key 
molecules that control their development and examine the contribution 
of each dc compartment to skin immunity. Preliminary data suggest that 
a wave of LC precursors seed the epidermis during embryonic life. Thus 
in aim 1, we propose to ex the potential of these embryonic precursors 
to maintain LC homeostasis throughout life. Mice that are deficient 
for MCSFR or tgfb1 lack epidermal LCs but the exact role of MCSF and 
tgfb1 in LC ontogeny is unknown. In this aim, we propose to examine 
how these molecules control LC development. Preliminary data also 
suggest that distinct precursors and differentiation pathways control 
the development of dermal langerin+ and dermal langerin-DCs. Thus in 
aim 2, we propose to identify the dedicated precursor and the 
mechanisms that control the development of dermal dc subsets. Finally, 
we believe that such complex dc network has developed to ensure skin 
integrity and in aim 3, we propose to examine the contribution of each 
DC compartment to skin immunity. 

Grant project title 40: Protein kinase A-dependent regulation of T 
cell accumulation in Lupus: 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $407,000; 
Grantee organization: 
Wake Forest University Health Sciences: 
Winston-Salem, NC 27157: 
Grant category: Existing applications; 
Abstract description: Establishing how deficient PKA-I activity 
results in abnormal T cell effector functions is a key step in 
understanding the etiopathogenesis of T cell dysfunction in SLE. In T 
cells from normal subjects, IL-2 induced IL-13+ cell accumulation in 
vitro is inhibited by the strong PKA activator PGE2, whereas the weak 
PKA activator beta-agonist causes increased accumulation. In SLE 
subjects with a severe defect in PKA activity, both PGE2 and ISO cause 
a profound increase in IL-2 induced IL-13+ cell accumulation. This R21 
application proposes to clarify the effect of defective PKA on 
regulatory features of T cell accumulation in SLE subjects. The 
hypothesis is that the subpopulation of SLE subjects with defects in 
PKA activity has exaggerated accumulation of type 2 cells when 
stimulated by beta-agonist and PGE2. Further hypothesis is that 
experimental knockdown/expression of the PKA RI¿-subunit is sufficient 
to cause/reverse this effect. These hypotheses will be tested using a 
highly interpretive in vitro model and a well characterized cohort of 
SLE subjects. Results from these studies will provide novel insight 
into the regulation of T cell development of interest to the basic 
science of T cell biology, and advance our understanding of immune 
system regulation in SLE. 

Grant project title 41: HIV-1 Replication and Pathogenesis in Vivo; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $711,553; 
Grantee organization: 
University of North Carolina Chapel Hill: 
Office of Sponsored Research: 
Chapel Hill, NC 27599: 
Grant category: Existing applications; 
Abstract description: The goals of this project are to define how HIV-
1 interacts with pDC and to elucidate the role of pDC cells in HIV-1 
replication and pathogenesis. As the major sensor of viral infections, 
altered pDC level/activity may play a critical role during HIV-1 
disease progression. However, the role of pDC cells in HIV infection 
and pathogenesis is poorly understood, mainly due to the lack of 
robust in vivo models. The DKO-hu HSC model is ideal for this purpose. 
With a stable functional human immune system, functional pDC cells are 
developed in normal proportion in all lymphoid organs in DKO-hu mice. 
HIV-1 establishes persistent infection, with immune hyperactivation 
and depletion of human CD4 T cells. We have also shown that, during 
HIV-1 infection, PDC cells are productively infected, activated, 
depleted and functionally impaired in DKO-hu HSC mice. HIV-1 with the 
pathogenic R3A Env also efficiently activates PDC in vitro, correlated 
with its high binding affinity to CD4 receptor and coreceptors. Based 
on our preliminary findings and reports from SIV-infected monkeys or 
HIV-infected patients, I postulate that HIV-1 intimately interacts 
with PDC cells, and chronic engaging of PDC during persistent HIV 
infection will deplete or impair PDC activity. The reduced or altered 
PDC activity contributes to chronic HIV infection, hyper-immune 
activation and AIDS progression. First, we will investigate the 
proliferation and survival of pDC cells during early and late-chronic 
HIV-1 infection in DKO-hu mice (SA1a). Second, we will define the role 
of each relevant receptor (CD4, CCR5, CXCR4, BDCA2, TLR7 and TLR9) in 
pDC activation with genetic approaches. In addition, we will also 
define the signaling defects in pDC cells induced by HIV infection, by 
genetically analyzing the candidate signaling pathways (SA2a). Third, 
we will treat DKO-hu mice with the pDC-specific ILT7 mAb conjugated 
with the Saporin toxin, which specifically depletes pDC, to test the 
role of pDC during infection (SA3c). We will thus focus on the most 
fundamental questions of pDC cells in HIV pathogenesis. Elucidation of 
the mechanism by which HIV-1 interacts with pDC cells and their role 
in HIV-1 infection and AIDS pathogenesis will facilitate not only our 
understanding of pDC biology in HIV pathogenesis, but also development 
of novel therapeutic strategies. 

Grant project title 42: Long Polar Fimbriae of Attaching and Effacing 
Escherichia coli; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $20,101; 
Grantee organization: 
University of Texas Medical BR Galveston: 
301 University Blvd: 
Galveston, TX 77555: 
Grant category: Supplements and revisions; 
Abstract description: The expression of Attaching and Effacing 
Escherichia coli (AEEC) virulence factors is a tightly regulated 
process, and, in some cases, the identification of these factors has 
been difficult because they are either repressed in vitro or the 
conditions of expression are unknown. While it is evident that 
expression of certain virulence factors is strictly associated with 
human disease, the additional factors present in AEEC strains that are 
linked to their pathogenic process remain unclear. Lack of a full 
understanding of how the genes encoding these additional virulence 
factors are controlled is important, because, without this knowledge, 
we are unlikely to understand the overall pathogenic properties of 
AEEC strains. Thus, our objective is to determine how the Long Polar 
(LP) fimbriae in AEEC strains contribute to pathogenesis and to use 
these fimbrial-encoding genes as markers to detect virulent strains. 
The central hypothesis is that, in addition to the already 
characterized colonization factors (e.g., intimin-mediated adhesion), 
AEEC strains possess a highly regulated LP fimbriae, that plays a role 
in the colonization process, and although the genes encoding these 
fimbriae are widely distributed in pathogenic E. coli strains, some LP 
fimbriae types are found exclusively in specific AEEC strains. We will 
test this hypothesis through three specific aims, which are to: (1) 
Define whether Ler and H-NS act as a selective silencing/anti-
silencing defense system that controls LP fimbriae expression in AEEC 
strains; (2) Identify the regulatory protein(s) controlling LP 
fimbriae expression in atypical EPEC and determine in a rabbit model 
the function of LP fimbriae during colonization; and (3) Characterize 
the distribution of the LP fimbrial gene clusters among AEEC strains 
and determine whether certain LP fimbrial subunit types are reliable 
markers of different pathogenic AEEC strains. To accomplish our aims, 
we will fully characterize the functions of Ler, H-NS, and atypical 
enteropathogenic E. coli-encoded regulators under in vitro and in vivo 
(infant rabbit colonization model) conditions and perform a detailed 
study of prevalence of the lpf genes in specific subsets of pathogenic 
AEEC strains. Our research work is innovative because it capitalizes 
on our findings regarding novel colonization factors in AEEC strains 
and their potential application in therapeutics and diagnostics. The 
results from studies of the regulatory networks controlling LP 
fimbriae expression have significance, because we will be able to 
identify fundamental differences to explain the tissue tropism of 
different AEEC strains and to determine whether silencing of LP 
fimbriae is an example of a defense system that AEEC strains have 
against horizontally acquired genes. In addition, the use of the 
rabbit model will give us new insight into the pathogenesis and 
colonization properties of AEEC strains. An understanding of the 
mechanisms underlying AEEC colonization to the gastrointestinal tract 
will not only further our knowledge of the pathogenesis of these 
organisms but also provide opportunities for reducing infection rates 
and improving treatment options against these biological agents 
classified as category B pathogens due t their potential use as a food 
safety threat. 

Grant project title 43: Plasmacytoid Dendritic Cells in HIV 
Pathogenesis; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $377,770; 
Grantee organization: 
Univ. of Med/Dent of NJ-NJ Medical School: 
185 S Orange Avenue: 
Newark, NJ 07107: 
Grant category: Supplements and revisions; 
Abstract description: Deficient production of interferon-a (IFN-a) by 
natural IFN-producing cells (NIPC) is observed in patients with 
advanced HIV-1 infection. This deficient IFN-a production was found to 
be associated with, and predictive of, susceptibility to opportunistic 
infections. Although long-suspected to be a dendritic cell, progress 
was somewhat hampered by the lack of a definitive phenotype for the 
NIPC. NIPC have now been demonstrated to be identical to the 
plasmacytoid dendritic cell (PDC). PDC's are believed to be important 
not only as professional IPC but also as vital links between innate 
and adaptive immunity. Deficient IFN-a production in HIV infection 
results from both decreases in numbers of circulating PDC as well as 
dysfunction in those cells present. This current study is organized in 
five specific aims; the first three involve studies of the basic 
biology of the PDC and the last two apply what has been learned about 
the function of PDC's to understand how they become deficient in HIV 
infected patients. Peripheral blood PDC's express very high 
constitutive levels of the transcription factor, IRF-7. These 
observations will be extended to evaluate the expression and function 
of the IRF-7 in PDC's in different anatomical sites and determine the 
roles of IRF-7 vs. IRF-3 and IRF-5 in these cells. Cross-linking of 
receptors on the surface of PDC leads to down-regulation of their 
ability to produce IFN-a, a phenomenon that may also have 
physiological relevance in the HIV-infected patients. Studies are 
proposed to understand the mechanisms of this down-regulation and 
determine whether other functions carried out by PDC such as 
production of TNF-a and chemokines is similarly affected by the 
receptor crosslinking. Production of IFN-a by PDC's does not require 
infection of the cells with virus; rather uptake of material by 
endocytosis appears to trigger the generation of IFN-a. Using 
fluorescent labeled infected cells or virus and confocal microscopy, 
the fate of the endocytosed material in vivo will be determined. In 
studies to better understand the mechanisms of deficiency in PDC in 
HIV-infected patients, studies will be undertaken to determine whether 
PDC's are infected with HIV in vivo and whether they traffic from the 
blood to sites in the tissues. Finally studies are proposed to 
evaluate other functions of the PDC in HIV-1 infected patients 
including cytokine and chemokine production and activation of T cells 
as well evaluation of the IRF-7 function in these cells. 

Grant project title 44: Regulation and Action of APOBEC3G; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $13,122; 
Grantee organization: 
J. David Gladstone Institutes: 
San Francisco, CA 94158: 
Grant category: Supplements and revisions; 
Abstract description: Apolipoprotein B mRNA editing enzyme, catalytic 
polypeptide-1 like 3G (APOBEC3G, A3G) corresponds to a host-derived 
cytidine deaminase that displays potent anti-retroviral activity. When 
incorporated into budding HIV virions, the A3G enzyme massively 
mutates nascent HIV DNA produced during reverse transcription in the 
next target cell thereby halting HIV growth. HIV counters these 
effects of A3G through its Vif gene product, which promotes 
accelerated proteasome-mediated degradation and partially impaired de 
novo synthesis of A3G. The intracellular depletion of A3G makes the 
antiviral enzyme unavailable for incorporation into progeny virions. 
Our recent studies have unveiled a second antiviral action of A3G 
operating in resting CD4 T-cells. In these T-lymphocytes, cellular A3G 
functions as a highly active post-entry restriction factor blocking 
the growth of both wild type and deltaVif forms of HIV. Whether this 
"Vif-resistant" anti-HIV defense mediated by A3G involves cytidine 
deamination or a different mechanism is currently unknown. Further, 
the mechanism by which this post-entry restricting function of A3G is 
forfeited when T-cells are activated remains incompletely understood. 
Similarly, little is known about how host cells safeguard their own 
DNA from the mutagenic effects of A3G. Finally, it remains unknown 
whether A3G exerts other key functions beyond these antiviral effects. 
In Specific Aim 1, experiments will be performed to decipher how A3G 
and the closely related A3F and A3B antiviral enzymes are regulated in 
cells. In Specific Aim 2, the mechanism of A3G action as a post-entry 
restriction factor in resting CD4 T-cells, the range of viruses 
affected by this restriction, and potential similar functions of A3F 
will be delineated. Finally, in Specific Aim 3, studies will be 
conducted to assess whether A3G mediates important nonantiviral 
functions in mammalian cells. These experiments will involve the 
preparation and analysis of mice lacking the functional analogue of 
the A3G gene. Together, this program of proposed experimentation 
promises to enrich our understanding of the biology of A3G as well as 
the related A3F and A3B enzymes. With such understanding, new 
therapeutic strategies for inhibiting HIV growth could emerge. 

Grant project title 45: Structure Studies on Proteins That Modulate IL-
10 Action; 
Administering IC: National Institute of Allergy and Infectious 
Diseases; 
Grant award size: $147,589; 
Grantee organization: 
University of Alabama at Birmingham: 
1530 3rd Avenue South: 
Birmingham, AL 35294: 
Grant category: Supplements and revisions; 
Abstract description: IL-10 is a multifunctional cytokine that 
regulates complex immune responses. Its normal function is to protect 
the host from uncontrolled inflammatory responses. However, IL-10 has 
also been implicated as an autocrine growth factor in several B-cell 
malignancies and stimulates B-cell mediated autoimmune disease. The 
normal and pathological functions of IL-10 are initiated by IL-10 
receptor engagement and assembly into a signaling competent IL-10/IL- 
10R1/IL-10R2 complex. In addition to cellular IL-10 (clL-10), Epstein 
Barr virus (EBV) and cytomegalovirus (CMV) harbor viral IL-10 mimics 
(ebvlL-10 and cmvlL-10) in their genomes that activate the IL-10 
signaling complex, resulting in overlapping and distinct biological 
properties. In the past funding period, we determined crystal 
structures of clL-10, cmvlL-10, and ebvlL-10 bound to the high 
affinity IL-10R1 chain. In this proposal we will use surface plasmon 
resonance, site-directed mutagenesis, NMR spectroscopy, X-ray 
crystallography, and FRET methods to study cellular and viral IL-10 
receptor interactions. These studies will be complemented by the 
analysis of the cellular IL-10 homologs IL-22 and IL-20. The long term 
goal of this proposal is to derive a quantitative 
structural/computational model of IL-10 family signaling that might 
explain how cellular and viral IL-10s shape immune responses and allow 
the rational design of cytokine therapeutics. 

Source: NIH. 

Note: The grant abstract description was reprinted, with permission, 
from the NIH RePORT Recovery Act page, [hyperlink, 
http://report.nih.gov/recovery/index.aspx] (accessed May 5, 2010) 
(further republication of the abstracts may require permission from 
the respective copyright holders). 

[End of table] 

[End of section] 

Appendix II: GAO Contact and Staff Acknowledgments: 

GAO Contact: 

Linda T. Kohn, (202) 512-7114 or kohnl@gao.gov: 

Staff Acknowledgments: 

In addition to the contact named above, Will Simerl, Assistant 
Director; N. Rotimi Adebonojo; Peter Mangano; Lisa Motley; and Krister 
Friday made key contributions to this report. 

[End of section] 

Footnotes: 

[1] Pub. L. No. 111-5, 123 Stat. 115 (2009). 

[2] The remaining $1.8 billion in Recovery Act funding was designated 
for repairs, improvements, and construction, as well as scientific 
equipment. The Recovery Act appropriated $700 million for CER to the 
Agency for Healthcare Research and Quality, $400 million of which was 
required to be transferred to NIH's Office of the Director (OD). 
According to NIH officials, these funds are managed centrally by the 
NIH OD and coordinated with additional CER funding within HHS. CER 
compares the benefits and harms of different interventions and 
strategies to prevent, diagnose, treat, and monitor health conditions. 

[3] The fiscal year 2009 appropriations for NIH totaled $30.5 billion, 
of which more than 80 percent was used for funding extramural research. 

[4] The Recovery Act also provided for the transfer of funds to the 
Common Fund, which is located within the OD and supports crosscutting, 
trans-NIH programs that require participation by at least two ICs or 
would otherwise benefit from strategic planning and coordination. 

[5] Pub. L. No. 111-5, § 1603, 123 Stat. 115, 302 (2009). While NIH 
must obligate all Recovery Act funds by the end of fiscal year 2010, 
the project end dates may occur after fiscal year 2010. As with other 
grants, Recovery Act grants are generally funded in annual increments--
called budget periods--over the course of the length of the project-- 
called project periods. Funding for each budget period is contingent 
on the availability of funds and satisfactory progress of the project. 

[6] For this report, we use the term "extramural grants" or 
"extramural research" when referring to NIH extramural scientific 
research grants. We excluded from our analysis grants or contracts 
awarded by NIH for repairs, improvements, and construction, as well as 
scientific equipment. 

[7] NCI, NIAID, and NHLBI received about 15 percent, 14 percent, and 9 
percent of the Recovery Act scientific research funds, respectively. 

[8] Twenty-four ICs and the OD, including the Common Fund, received 
Recovery Act funds. Three centers do not fund extramural scientific 
research and did not receive funding (Center for Scientific Review, 
Center for Information Technology, and the Clinical Center). 

[9] For this report, grant award refers to Recovery Act funds that had 
been awarded by NIH to grantees in fiscal years 2009 and 2010, as well 
as funds that have been committed, that is, expected to be awarded in 
future years subject to the availability of funds and satisfactory 
progress of the project. 

[10] For this report, the term "publicly available" information refers 
to information disseminated on NIH's and the three ICs' Internet Web 
sites. NIH uses its Web site as its primary means of communicating 
information about grants. 

[11] For example, to avoid the potential for double counting we 
removed three records for grants awarded in fiscal year 2009 that 
contained separate award actions for the same grant in fiscal year 
2010. We removed one grant record because it reflected the fact that 
the grant recipient transferred from one university to another. We 
also compared the data from a random sample of grants in the data file 
to the same grants in a publicly-available data file for accuracy. 

[12] NIH also supports intramural research, which is performed by NIH 
scientists in NIH laboratories. 

[13] The three centers that do not fund extramural scientific research 
and do not receive separate appropriations (Center for Scientific 
Review, Center for Information Technology, and the Clinical Center) 
are funded through the NIH Management Fund, which is funded using a 
portion of other NIH appropriations. See 42 U.S.C. § 290. 

[14] See 42 U.S.C. §§ 282(b)(9) (the Director of NIH must ensure that 
NIH research undergoes peer review and advisory council review); 
289a(a) (peer review); 289a-1(a)(2) (advisory council review). 

[15] GAO, National Institutes of Health: Completion of Comprehensive 
Risk Management Program Essential to Effective Oversight, [hyperlink, 
http://www.gao.gov/products/GAO-09-687] (Washington, D.C.: Sept. 11, 
2009). 

[16] See 42 C.F.R. § 52h.7 (2009). 

[17] Peer review groups are to assess each proposed research project 
taking into account the following criteria, among other pertinent 
factors: (a) its significance, (b) the adequacy of its approach and 
methodology, (c) its innovativeness and originality, (d) the 
qualifications and experience of its principal investigator and staff, 
(e) the scientific environment and reasonable availability of 
resources for it, (f) the adequacy of its plans to include both 
genders, minorities, children, and special populations as appropriate 
for its scientific goals, (g) the reasonableness of its budget and 
duration, and (h) the adequacy of its protections for humans, animals, 
and the environment. 42 C.F.R. § 52h.8 (2009). 

[18] For this report, we use the term "priority score" to refer to the 
NIH impact/priority score. NIH began using the term impact/priority 
score to reflect changes to its scoring system implemented in 2009. 

[19] For this report, we use the term "advisory council" to refer to 
an advisory council or board. 

[20] 42 U.S.C. § 284a. Although the law setting forth the requirements 
for advisory councils is specific to institutes, each center that 
funds extramural research has an advisory council substantially 
similar to those of the other institutes. See 42 U.S.C. §§ 287a 
(National Center for Research Resources), 287c-21(b) (National Center 
for Complementary and Alternative Medicine). 

[21] Advisory councils also include ex officio members, who are 
nonvoting. Voting members generally serve 4-year terms. At the NCI, 
the President appoints voting advisory council members, and the 
members serve 6-year terms. For all other advisory councils, the 
Secretary of the Department of Health and Human Services appoints 
voting members. 

[22] According to NIH officials, the advisory council may concur with 
the initial peer review group's assessment, may decide not to 
recommend an application, or may recommend deferral of an application 
and refer it back to the initial peer review group for re-review. 

[23] NIH may not approve or fund any application unless it has been 
recommended for approval by a majority of the members of the initial 
peer review group and a majority of the voting members of the advisory 
council. The initial peer review groups recommend applications for 
approval by means of the scoring system. 42 U.S.C. § 289a-1(a)(2). 

[24] Recovery Act funding announcements are publicly available 
documents used by NIH to announce an intention to award grants, 
usually through a competitive process. 

[25] For applications for Challenge grants the initial review was 
conducted by the Center for Scientific Review, while for applications 
for Grand Opportunity (GO) grants the initial review was conducted by 
a peer review group convened by the appropriate IC. The second-level 
peer review for both grant types was conducted by the IC's advisory 
council. 

[26] The Challenge Grant program focuses on health and science 
problems such as cancer and autism. The GO grant program supports high-
impact ideas that require significant resources for a discrete period 
to lay the foundation for new fields of investigation. 

[27] The payline is a threshold that is determined by the number of 
extramural grant applications that an IC anticipates funding that 
year. One IC reported that it extended its payline from the 16th 
percentile to the 25th percentile of grant applications as ranked by 
priority score. Another IC extended its payline from the 12th 
percentile to the 25th percentile, and the third extended its payline 
from the 15th percentile to the 25th percentile. 

[28] These states are identified in NIH's Institutional Development 
Award (IDeA) program. According to NIH, IDeA is designed to broaden 
the geographic distribution of NIH funding for biomedical and 
behavioral research. The program fosters health-related research and 
enhances the competitiveness of investigators at institutions located 
in states in which the aggregate success rate for applications to NIH 
has historically been low. 

[29] For this report, grant award refers to Recovery Act funds that 
had been awarded by NIH to grantees in fiscal years 2009 and 2010, as 
well as funds that have been committed, that is, expected to be 
awarded in future years subject to the availability of funds and 
satisfactory progress of the project. NIH officials reported that the 
remaining extramural grant funds will be awarded by the end of fiscal 
year 2010. 

[30] NIH made 4,044 extramural grant awards for grant applications 
that had previously been peer reviewed by NIH but had not received NIH 
funding; 1,544 extramural grant awards for applications from Recovery 
Act-specific funding opportunity announcements, such as the Challenge 
and GO grants; and 8,564 awards for existing extramural grants in the 
form of administrative supplements and competitive revisions to 
current active grants. 

[31] The $29.6 million grant award funded a large-scale research 
project about the efficacy and effectiveness of physical activity on 
the health outcomes of older Americans. 

[32] Specifically, according to an NIH official, 93 percent, 98 
percent, and 97 percent of Recovery Act extramural grants at NCI, 
NHLBI, and NIAID, respectively, were for durations of 2 years or less. 

[33] According to an NIH official, the three NIH ICs that GAO reviewed 
committed a total of about $181 million dollars in future annual 
appropriations for Recovery Act extramural grants with durations of 
greater than 2 years, subject to the availability of funds and 
satisfactory progress of the projects. 

[34] Early-stage principal investigators are new investigators within 
10 years of completing their terminal research degree or medical 
residency. 

[35] Clinical trials are biomedical or behavioral research studies of 
human subjects designed to answer specific questions about biomedical 
or behavioral interventions (drugs, treatments, devices, or new ways 
of using known drugs, treatments, or devices). 

[36] See Dollars Awarded by State for 2009 at [hyperlink, 
http://report.nih.gov/award/trends/State_Congressional/StateOverview.cfm
] (accessed Apr. 5, 2010). 

[37] In addition to information communicated by NIH, NIH policy states 
that grantees should make the results and accomplishments of their 
grant activities available to the research community and to the public 
at large. The Omnibus Appropriations Act of 2009 made the policy a 
permanent requirement. See Pub. L. No. 111-8, div. F, tit. II, § 217, 
123 Stat. 524, 782. In addition, NIH endorses the sharing of final 
research and the timely release and sharing of final research data 
from NIH-supported studies for use by other researchers. NIH officials 
reported that this policy also applies to extramural grants made with 
Recovery Act funds. 

[38] NIH officials reported that NIH also used other electronic and 
nonelectronic methods, such as radio, television, and newspaper, for 
disseminating information about Recovery Act grant awards. 

[39] For more information, see the RePORT Recovery Act page at 
[hyperlink, http://report.nih.gov/recovery/index.aspx] (accessed May 
3, 2010). 

[40] The Web-based system allows users to generate reports on NIH 
expenditures and the results of NIH-supported research, such as budget 
and spending and funded organizations. 

[41] Information on NIH Recovery Act extramural grant awards is 
available at [hyperlink, http://recovery.nih.gov/] (accessed August 2, 
2010), as well as at [hyperlink, 
http://www.recovery.gov/Pages/home.aspx] (accessed June 16, 2010). 

[42] See NIH Recovery Act Investment Reports at [hyperlink, 
http://report.nih.gov/_recovery/investmentreports/ARRAInvestments.aspx?k
ey=] (accessed June 3, 2010). 

[43] For example, see the NIH's Recovery Act Story Index page at 
[hyperlink, http://recovery.nih.gov/story.php]; NCI's Meet Some of the 
NCI Recovery Act Funded Researchers page at [hyperlink, 
http://www.cancer.gov/recoveryimpact/fundedresearchers/]; NHLBI's Meet 
the Scientists page at [hyperlink, 
http://www.nhlbi.nih.gov/recovery/researchers/index.php]; and NIAID's 
Recovery Act Success Stories page at [hyperlink, 
http://funding.niaid.nih.gov/ncn/recovery/impactsuccess.htm] (all 
accessed June 4, 2010). 

[44] See Recovery Act Releases at [hyperlink, 
http://recovery.nih.gov/news_releases.php] (accessed June 4, 2010). 

[45] In some cases, an extramural grant funded by the Office of the 
Director (OD) may be administered by an IC. 

[46] Information on NIH Recovery Act extramural grant awards is also 
available at [hyperlink, http://www.recovery.gov/Pages/home.aspx] 
(accessed June 16, 2010). 

[47] For this report, grant award size refers to Recovery Act funds 
that had been awarded by NIH to grantees in fiscal years 2009 and 
2010, as well as funds that have been committed, that is, expected to 
be awarded in future years subject to the availability of funds and 
satisfactory progress of the project. 

[End of section] 

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