RELEASE DATE:  April 22, 2004

PA NUMBER:  PA-04-098

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. Accordingly, this funding opportunity 
expires on the date indicated below. Replacement R01 (PA-06-186) and R21 (PA-06-187) 
funding opportunity announcements have been issued for the submission date 
of June 1, 2006 and submission dates thereafter. 

See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and 
AIDS-related R03 and R21 Applications.

EXPIRATION DATE:  March 2, 2006

Department of Health and Human Services (DHHS)

National Institutes of Health (NIH) 

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/NIH)
National Heart, Lung and Blood Institute (NHLBI)
National Institute on Aging (NIA)


o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

The National Institutes of Diabetes and Digestive and Kidney Diseases 
(NIDDK), the National Heart, Lung, and Blood Institute (NHLBI) and the 
National Institute on Aging (NIA) invite investigator-initiated Research 
Projects (R01 and R21) to investigate the life cycle of adipocytes and other 
cell types present in various fat depots, such as macrophages, neurons, and 
endothelial cells.  The goal of this initiative is to increase our 
understanding of the interactions among the cell populations in order to 
identify biomarkers of changes in cellular physiology and metabolism brought 
on by the obese state, which are truly associated with the development of co-
morbidities such as diabetes, atherosclerosis, and hypertension.  The long 
term goal of this initiative is to identify markers of obesity associated 
with disease risk that could yield new targets for therapeutics to disrupt 
this link.



Little is known about the factors that control where fat is deposited; 
distinguishing features of fat in different locations (visceral versus 
subcutaneous); regulation of the regenerative capacity of individual depots; 
and how paracrine and autocrine signals generated by different cell types 
present in a particular depot regulate its metabolic status.  While visceral 
obesity appears to be associated with increased morbidity, the basis of this 
association is not clear. 

Body Mass Index (BMI) has been the primary variable measured and used in 
studies linking obesity with several of its co-morbidities, including 
diabetes, hypertension, osteoarthritis, and cancer.  However, specific 
biomarkers of changes in cellular physiology and metabolism brought on by the 
obese state, which are truly associated with the development of each of these 
co-morbidities, are clearly needed.  
There is a need to obtain a more detailed picture of how the many cell types 
present in different fat depots (e.g. adult adipocytes, pre-adipocytes, 
stem/progenitor cells, tissue macrophages, neurons, and endothelial cells) 
interact with each, and sense and respond to the metabolic and inflammatory 
status of the entire organism.   

Objectives and Scope  

This program announcement requests investigator initiated studies designed to 
examine in detail the life cycle of adult fat cells and other cell types, 
such as macrophages, neurons, vascular smooth muscle and endothelial cells, 
within specific fat depots.  The goal is to identify novel biomarkers of 
changes in cellular physiology and metabolism brought on by the obese state, 
which are truly associated with the development of co-morbidities such as 
diabetes, atherosclerosis, and hypertension.  The long term goal of this 
initiative is to identify markers of obesity associated with disease risk 
that could yield new targets for therapeutics to disrupt this link.

The NIDDK, NHLBI and NIA intend to support investigator-initiated projects 
(R01s) and Exploratory/Developmental Research projects (R21s) that explore 
the fundamental mechanisms contributing to the heterogeneity of different fat 
depots and how these differences correlate with obesity and its associated 
morbidities.  Investigators applying to this program announcement are 
encouraged to use genome-wide studies (genomics, proteomics, lipidomics or 
metabolomics), advanced lineage tracing techniques, analytic methods, and 
state-of-the-art cell biology approaches to study the heterogeneity of 
individual fat depots.

Areas of research opportunities include but are not restricted to the 

o Measure and compare the turnover rates of adipocytes and tissue macrophages 
from various fat depots, and investigate if and how these turnover rates are 
impacted by the development of obesity, diabetes, hypertension, 
atherosclerosis, or aging.

o Develop mouse models of visceral obesity to use as tools to study the 
development of obesity.

o Examine the effects of cross transplantation of different fat depot types 
or transplantation of different depots into fatless mice as a means of 
learning more about the underlying differences between depots.

o Identify growth factors, extracellular matrix components, lipids, and/or 
other signaling molecules that influence the proliferative or metabolic state 
of endothelial cells, macrophages and adipocytes located in a particular fat 

o Identify surrogate markers unique to specific fat depots, such as visceral 
fat, that may correlate with the progression of obesity and associated 
morbidities in humans and animal models. 

o Use proteomic technologies to study differences in the inflammatory 
response to fat accumulation in various fat depots and the potential role of 
inflammation in the development and progression of obesity and its associated 

o Study and compare the production, regulation, secretion and function of 
hormones, cytokines, growth factors, lipids and/or other signaling molecules 
made by various cell type(s) in different fat depots, such as abdominal 
subcutaneous vs. visceral fat or fat tissues surrounding specific organs, 
such as kidney and heart, that may lead to cardiovascular or metabolic 

o Examine interrelationships among cells comprising the vasculature and other 
cell types within a fat tissue, whether these relationships differ among 
different fat depots, and how they may lead to vascular disorders.

o Investigate the role of adipocytes and other cell types found in fat tissue 
in angiogenesis and vasculogenesis.


This PA will use the NIH investigator-initiated Research Project Grant (R01) 
and the Exploratory/Development Research Grant (R21) award mechanisms.  As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  The total requested project period for an 
application submitted in response to this PA may not exceed 2 years for the 
R21 mechanism.  R21 grants will not be renewable; continuation of projects 
developed under this program will be through the R01 grant program.  

This PA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see https://grants.nih.gov/grants/funding/modular/modular.htm).   
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular budget format.  This program does 
not require cost sharing as defined in the current NIH Grants Policy 
Statement at https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations


Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   


Sharing Research Data:   All investigators responding to this PA should include 
a description of how final research data will be shared, or explain why data 
sharing is not possible.   

Sharing Research Resources:  NIH policy requires that grant awardee recipients 
make unique research resources readily available for research purposes to 
qualified individuals within the scientific community after publication 
[NIH Grants Policy Statement (https://grants.nih.gov/grants/policy/nihgps;  and 
(http://www.ott.nih.gov/policy/rt_guide_final.html).   Investigators responding 
to this PA should include a plan for sharing research resources that addresses 
how unique research resources will be shared or explain why sharing is not 

The adequacy of the data sharing plan and the resource sharing plan will be 
considered by IC Program Staff when making recommendations about funding 
applications.  IC Program Staff may negotiate modifications of the data and 
resource sharing plans with the Principal Investigator before recommending 
funding of an application.  The final version of the data sharing plan and the 
resource sharing plan negotiated by the Principal Investigator and IC Program 
Staff will become a condition of the award of the grant.  The effectiveness of 
the resource sharing will be evaluated as part of administrative review of each 
Non-competing Grant Progress Report (PHS 2590).


We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Carol Renfrew Haft, Ph.D.
Program Director, Adipocyte Biology
Division of Diabetes, Endocrinology and Metabolism
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Room 605
Bethesda, MD  20892-5460
Telephone:  (301) 594-7689
FAX:  (301) 480-3503 
E-mail: cr84g@nih.gov

Winnie Barouch, Ph.D.
Vascular Biology Research Program
Division of Heart and Vascular Diseases
National Heart, Lung and Blood Institute
6701 Rockledge Drive, Suite 10193
Bethesda, MD  20892-7956
Telephone:  (301) 435-0560
FAX:  (301) 480-2849 
E-mail: wb37j@nih.gov

David B. Finkelstein, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231
Bethesda, MD 20892-9205
Telephone:  (301) 496-7847
FAX:  (301) 402-0010 
E-mail: df18s@nih.gov 

o Direct your questions about financial or grants management matters to:

Denise Payne
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 733 
Bethesda, MD  20892-5456
Telephone:  (301) 594-8845
FAX:  (301) 480-3504
E-mail: dp43@nih.gov


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html 
in an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.

The program announcement title and number must be typed on line 2 of the face 
page of the application form and the YES box marked.  Also indicate if the 
application is an R01 or R21.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at https://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

requesting up to $250,000 per year in direct costs must be submitted in a 
modular budget grant format.  The modular budget grant format simplifies the 
preparation of the budget in these applications by limiting the level of 
budgetary detail.  Applicants request direct costs in $25,000 modules.  
Section C of the research grant application instructions for the PHS 398 
(rev. 5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at 

INSTRUCTIONS FOR R21 APPLICATIONS:  This program announcement allows the 
submission of R21 (Exploratory/Developmental Research Grant) applications.  
R21 applications must adhere to the page and budgetary limitations described 
in the trans-NIH R21 program announcement (PA03-107) available at: 

Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your         
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff member       
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be mailed on or before the receipt 
dates described at 
https://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an unfunded version of an application 
already reviewed, but such application must include an Introduction 
addressing the previous critique.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.   Appropriate scientific review groups 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the appropriate national advisory council 
or board.  


The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate each application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application’s overall score, weighting them as appropriate for each 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The application does not need to be strong in all categories to be judged 
likely to have major scientific impact and thus deserve a high priority 
score.  For example, an investigator may propose to carry out important work 
that by its nature is not innovative but is essential to move a field 

SIGNIFICANCE: Does this study address an important problem? If the aims of 
the application are achieved, how will scientific knowledge be advanced? What 
will be the effect of these studies on the concepts or methods that drive 
this field?

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project? Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

INNOVATION: Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?

INVESTIGATOR: Is the investigator appropriately trained and well suited to 
carry out this work? Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers (if any)?

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success? Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements? Is there evidence of institutional support?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below). 

plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  


Sharing Research Data 

All applicants  are expected to include a data sharing plan in their 
application regardless of the amount of direct costs. The reasonableness of 
the data sharing plan or the rationale for not sharing research data will be 
assessed by the reviewers. However, reviewers will not factor the proposed 
data sharing plan into the determination of scientific merit or priority 

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.


Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 

SHARING RESEARCH DATA: Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing or state why this is not possible. 
https://grants.nih.gov/grants/policy/data_sharing  Investigators should seek 
guidance from their institutions, on issues related to institutional 
policies, local IRB rules, as well as local, state and Federal laws and 
regulations, including the Privacy Rule. Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the 
scientific merit or the priority score.

the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research. This policy results from the NIH Revitalization Act of 1993 (Section 
492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
a complete copy of the updated Guidelines are available at 
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at http://stemcells.nih.gov/index.asp and at  
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 

Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information”, 
the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites. Furthermore, we 
caution reviewers that their anonymity may be compromised when they directly 
access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.