RELEASE DATE:  July 28, 2003

PA NUMBER: PA-03-156

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 using 
the electronic SF424 (R&R) application. Accordingly, this funding opportunity 
expires on the date indicated below. Replacement R01 (PA-06-175) and R21 (PA-06-176) 
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

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
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 Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
and the National Institute on Aging (NIA) invite investigator-initiated 
research grant applications that will investigate crosstalk in insulin 
responses at molecular, cellular, and physiological levels. The purpose of 
this initiative is to stimulate novel and innovative research into the 
fundamental mechanism(s) of action of the insulin receptor in target tissues 
in the context of other cellular receptors and signaling pathways, and to 
broaden our understanding of how insulin signals act to regulate coordinated 
responses between and among insulin responsive tissues. Of particular 
interest is how such signaling interactions may affect the development and/or 
progression of diabetes and its complications.  

This program announcement replaces PAS 99-112.



Diabetes currently affects an estimated 16 million Americans, and is the sixth 
leading cause of disease-related death in the US. With the diagnosis of 
approximately 800,000 new cases each year, the health and economic burden of 
diabetes continues to escalate. Given the magnitude of the problem and its 
enormous impact on patient health and welfare, there is an urgent need to 
define the factors contributing to diabetes onset and severity, and to 
identify new potential therapeutic targets. A defining feature of Diabetes 
mellitus is the inappropriate regulation of serum glucose levels.  Both type 1 
and type 2 diabetes are associated with insulin deficiency, with type 2 
diabetes further complicated by cellular resistance to insulin action. 
Obesity, a condition that itself is rising in prevalence, is a major risk 
factor for development of both insulin resistance and type 2 diabetes. While 
the precise relationship between obesity, type 2 diabetes, and insulin 
resistance remains under investigation, emerging data suggests that changes in 
insulin receptor regulated signaling pathways are involved.  

The insulin receptor plays a dominant role in mediating insulin's effects. 
However, insulin target tissues also respond to hormones, growth factors and 
cytokines that have the potential to modify insulin responses. Receptors for 
many of these soluble factors initiate signals that may overlap or modulate 
insulin-stimulated biochemical pathways, and in this way impact the quality or 
quantity of the insulin response. For example, members of the growth factor, 
cytokine, and G-protein coupled receptor families are all expressed in various 
combinations in insulin responsive tissues.  Stimulation of these receptors 
and the signaling pathways they regulate has the potential to alter the 
strength, duration, or character of the insulin response. Thus, signals 
initiated via the insulin receptor must be interpreted by cells in the context 
of multiple biochemical signals that arise in the complex microenvironment 
found in insulin-responsive tissues. Intracellular interactions between 
insulin dependent biochemical events and signals transduced via other 
signaling pathways, or "crosstalk", may occur at multiple levels, including at 
the level of receptor function, substrate availability, signal flow through 
downstream pathways, and/or integrated control of gene expression. Cross-talk 
also occurs between insulin-responsive tissues, with recent evidence 
suggesting that insulin signals elicited in one target tissue impact responses 
in other organs and at distant sites.      

While significant progress has been made in defining the biochemistry of the 
insulin-response pathway, in documenting insulin-regulated changes in gene 
expression and in elucidating the crosstalk that occurs between insulin 
responsive organs, important scientific gaps remain to be explored. For 
example, our understanding of how a cell's complex biochemical history may 
modify subsequent responses to insulin, and of how multiple environmental cues 
regulate insulin action within and between target tissues in vivo, remains 
rudimentary. Information generated via these and related studies of signaling 
crosstalk within and between insulin-responsive tissues has the potential to 
provide important insights into the mechanisms that underlie diabetes 
pathophysiology, and may have important implications for the design of new 
therapeutics to treat diabetes and its complications.

Objectives and Scope

This Program Announcement solicits investigator-initiated research projects 
that will define the mechanistic basis of crosstalk between the insulin 
receptor signaling pathway and other signaling pathways, with the goal of 
defining how insulin action is influenced by the complex microenvironment 
found in insulin responsive tissues.   

Appropriate topics for investigation under this PA would include, but are not 
limited to: 

o determining the specificity of signaling through the insulin receptor, 
including delineation of metabolic versus mitogenic responses;  

o signaling through receptors for other soluble factors found in insulin 
target tissues, including growth factors and cytokines, and potential 
modifying effects of these soluble factors on insulin action, diabetes 
pathophysiology and its complications; 

o signals initiated by adhesion molecules such as integrins in insulin-
responsive tissues, including receptors involved in regulating intercellular 
communication and interactions with the extracellular matrix, and the impact 
of these signals on insulin responses in vitro and in vivo. 

o interactions between and among insulin responsive tissues, including 
factors mediating organ-specific crosstalk in insulin-driven responses; 

o age-related changes in insulin sensitivity at the level of the insulin 
receptor and its activating ligand(s), insulin receptor signaling pathway, 
cross-talk with other intracellular signaling pathways, and/or altered gene 
and protein expression profiles in insulin-responsive tissues;

o factors regulating cell surface expression of functional insulin receptors 
and other cell surface receptors in diabetes and its complications; 

o interactions between and among transcription factors that mediate the 
effects of insulin on gene expression: cross-talk with transcription factors 
responding to other signaling pathways; 

o signaling cross-talk between the insulin receptor and nuclear receptors, 
including effects on development and/or progression of diabetes and its 

o identification of factors involved in cell signaling that may cause 
resistance to insulin action in insulin-sensitive cells (e.g. muscle, 
adipose) and novel approaches to overcome or bypass such resistance; 

o genomic, proteomic, and other state-of-the-art biochemical approaches to 
identify novel factors associated with insulin action in target tissues, 
including putative targets for therapeutic intervention; 

o structural biology of cell surface receptors and signal relay molecules 
that transduce or modify insulin actions, including enzymes, protein 
scaffolds, and higher-order complexes capable of integrating signals 
generated by receptor cross-talk in insulin-responsive cells; 

o the mechanism of action of non-peptide receptor analogs and their potential 
efficacy as therapeutic agents.

Information generated via these and related studies of signaling crosstalk in 
insulin-responsive tissues has the potential to provide important insights 
into the mechanistic basis of diabetes pathophysiology. These insights may in 
turn have important implications for the design and implementation of new 
therapeutics to treat diabetes and its complications


This PA will use the National Institutes of Health (NIH) research project 
grant (R01) and the Exploratory/Development Research Grant (R21) award 
mechanisms.  As an applicant, you will be solely responsible for planning, 
direction, and executing the proposed project. 

This PA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see  
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular format. This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at  

The R01 award represents an investigator-initiated research grant designed to 
support a discrete, specified research project performed by a principal 
investigator. R01 applications may request up to $250,000 per year in direct 
costs for a maximum of five years.

R21 (Exploratory/Developmental) grants (see

The R21 mechanism is intended to encourage new exploratory/developmental 
research projects by providing support for the early stages of their 
development.  Awards are made to demonstrate feasibility of a subsequent 
project and to obtain preliminary data testing innovative ideas.  Therefore, 
these grants are not renewable. Continuation of projects developed under this 
program will be through the regular research project grant mechanism (for 
example, R01).  These grants are not intended to support or supplement 
ongoing funded research of an established investigator, or to serve as an 
alternative mechanism of support for projects not receiving funding as 
competitive continuation applications.  The NIH Grants Policy statement 
applies to these awards.

An R21 application should have a research plan that does not exceed 15 pages.  
A two-year project period is the maximum period of support.  You may request 
a project period of up to two years with a combined budget for direct costs 
up to $275,000 for the two year period.  For example, you may request 
$100,000 in the first year and $175,000 in the second year.  The request 
should be tailored to the needs of your project.  Normally, no more than 
$200,000 may be requested in any single year. Little or no preliminary data 
are required. Up to five relevant published articles may be included as 
Appendix material, if desired.

Exploratory/developmental grant support is for new projects only; competing 
continuation applications will not be accepted.   Two revisions of a 
previously reviewed exploratory/developmental grant application may be 
submitted as defined in NIH Policy at


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
o Faith-based or community-based 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.   


Plan for Dissemination of Data and Biomaterials

Sharing of biomaterials, data, and software in a timely manner has been an 
essential element in the rapid progress that has been made in the genetic 
analysis of human diseases.  PHS policy requires that investigators make 
unique research resources available for research purposes to qualified 
individuals within the scientific community when they have been published 
(see the NIH Grants Policy Statement at  In 
addition, NIH recently released a statement on the sharing of research data 
that applies to all investigator-initiated applications with direct costs 
greater than $500,000 in any single year 

All applicants who respond to this PA must propose plans for sharing data and 
biomaterials generated through the grant.  Applicants should explain how 
funds for the storage and distribution of data and biomaterials will be 
obtained, and may request such funds in the budget of the application.  It is 
expected that the information to be shared will include clinical, diagnostic, 
and pedigree structure information.  Biomaterials to be shared should include 
patient DNA and cell lines.  When possible, data and biomaterials should be 
placed in databases or repositories that will permit their efficient 
distribution to investigators throughout the scientific community.  Rapid 
sharing of data and biomaterials is strongly encouraged.

The Initial Review Group will evaluate the proposed sharing plan and comment 
on its adequacy in an administrative note in the summary statement.  
Reviewers will not factor the proposed data-sharing plan into the 
determination of scientific merit or priority score.  NIH staff will consider 
the adequacy of the plan and determine whether the grant shall be awarded.  
The sharing plan as approved, after negotiation with the applicant when 
necessary, will be a condition of the award.


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:

Kristin Abraham, Ph.D.
Cell Signaling Program Director 
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 607
Bethesda, MD 20892-5460
Telephone:  (301) 451-8048
FAX:  (301) 480-3503

Frank Bellino, PhD
Biology of Aging Program 
National Institute on Aging 
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010

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

Randi Freundlich, R.D.
Grants Management Specialist
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 723
Bethesda, MD 20892-5456
Telephone:  (301) 594-8825 
FAX:  (301) 480-3504

Jeff Ball
Grants and Contracts Management Office 
National Institute on Aging 
Gateway Building, Room 2N212
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

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

initiated R21 applications must be submitted in a modular grant format. The 
modular 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 includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 

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 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 application already reviewed, but 
such application must include an Introduction addressing the previous 

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.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
( will evaluate applications for scientific 
and technical merit.  

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

o Receive a written critique
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 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 discuss the following 
aspects of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria 
in assigning the application's overall score, weighting them as appropriate 
for each application.  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 forward.

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. 

exploratory/developmental grant is a mechanism for supporting novel 
scientific ideas or new model systems, tools or technologies that have the 
potential to significantly advance our knowledge or the status of health-
related research.  Because the research plan is limited to 15 pages, an 
exploratory/developmental grant application need not have background material 
or preliminary information as one might normally expect in an R01 
application.  Accordingly, reviewers will focus their evaluation on the 
conceptual framework, the level of innovation, and the potential to 
significantly advance our knowledge or understanding.  Reviewers will place 
less emphasis on methodological details and certain indicators traditionally 
used in evaluating the scientific merit of R01 applications including 
supportive preliminary data. Appropriate justification for the proposed work 
can be provided through literature citations, data from other sources, or, 
when available, from investigator-generated data.  Preliminary data are not 
required for R21 applications.    


DATA SHARING:  The adequacy of the proposed plan to share data.
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. 

involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 

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 
them. This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

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

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). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at 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

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