RELEASE DATE:  July 14, 2003
RFA:  DK-03-021
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 

LETTER OF INTENT RECEIPT DATE:  October 20, 2003 and June 20, 2004

APPLICATION RECEIPT DATES:  November 20, 2003 and July 20, 2004

o Purpose of the RFA
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


Much of our understanding of the basic biology and function of the beta cell 
and the pancreatic islet comes from studies of immortalized cell lines and 
mouse tissue.  However, differences in the general structure and organization 
of mouse and human islets have been identified, and it remains uncertain if 
these structural differences reflect functional differences as well.  With 
the variable success in islet transplantation and the inability to use in 
vitro data to reliably predict islet engraftment and function, it is 
important to learn all that we can about the structure, organization, and 
signaling properties of human islets, and to compare and contrast these 
findings with those reported with rodent models of islet function used to 
date.  The information gained from these studies should increase our ability 
to develop new reagents for use in in vivo imaging studies of the human 
islet, to develop fingerprinting assays for use in predicting human islet 
transplant success, and to further develop cellular therapies for potential 
use in the treatment of type 1 diabetes.


Over the last 5 years the NIDDK has supported a number of initiatives 
designed to increase our basic knowledge of the development, structure, and 
function of the pancreatic beta cell, with the ultimate goal of improving 
treatment of diabetes and its complications.  

In 2002, the NIDDK sponsored a workshop "Beta Cell Biology in the 21st 
Century:  Engineering a Pathway to Greater Understanding".  An important goal 
of the workshop was to identify areas of research opportunity in the adult 
pancreatic beta cell.  In 2003, an NIH advisory meeting focused on pancreatic 
islet transplantation was also convened.  Two research priorities that 
emerged from these meetings were the need to obtain basic information about 
the general architecture and organization of human islets, and to develop a 
better functional definition of the characteristics of normal isolated human 
beta cells and human beta cells in their natural milieu in the islet.  To 
date, much of the information generated has come from cell lines derived from 
insulin-producing tumors (e.g., mouse and rat insulinomas, in modified 
neuroendocrine cells (e.g., mouse AtT20 cells, with mouse and rat islets/beta 
cells, and to a lesser degree from monkey islets. However, much of this 
important basic information is lacking for human beta cells and human 
pancreatic islets. 

In an effort to increase our understanding of the pancreatic beta cell, NIDDK 
has supported efforts to gather expression data from both mouse and human 
beta cells, and to generate cell type-specific cDNA tools for the research 
community. The Endocrine Pancreas Consortium Database 
(http://www.cbil.upenn.edu/EPConDB) now contains information on the genes 
expressed in cells of the pancreas identified by dbEST libraries from 
pancreatic tissues including 12 mouse and 7 human libraries generated by the 
Consortium.  Microarray chips based on the collection of 13,910 human 
pancreatic genes are presently being developed, and will be distributed in 
2004.  The information in this database, along with the cDNA reagents 
generated, should aid researchers in pursuing novel lines of investigation in 
the human beta cell. 

Other recent initiatives of the NIDDK, the National Center for Research 
Resources (NCRR), and the Juvenile Diabetes Research Foundation International 
resulted in the establishment of multiple centers throughout the country that 
isolate and distribute human islets for islet transplantation, clinical 
studies aimed at improving cell viability and engraftment, and for basic 
research purposes.  To learn more about obtaining islets for basic research 
purposes the coordinating center for the Islet Cell Resources may be 
contacted (see http://www.infosci.coh.org/icr/).

Objectives and Scope

This program announcement is intended to stimulate research focusing on the 
biology of human beta cells and human pancreatic islets.  Examples that 
illustrate possible areas of research are presented below. They are intended 
only to provide a broad direction for research and should be considered 
illustrative and not restrictive. Some potential topics are:

o Research on normal human pancreas structure including patterns of 
innervation and blood flow, especially as these parameters relate to islet 
structure, organization and function

o Studies of the distribution, numbers, and phenotypes of cells within the 
endocrine tissue, endothelium, and ducts of the normal human pancreas

o Studies designed to investigate the life cycle of human beta cells focusing 
on the roles of necrosis, apoptosis, and regeneration in controlling beta cell 

o Studies designed to determine surrogate markers of normal islet function or 
dysfunction that could be ultimately used for evaluating transplantation 
o Studies of the physiology and function of human islets, under defined 
conditions designed to simulate pathophysiologic processes or the 
transplantation setting

o Determine the transcriptional or protein profiles of purified or partially 
purified populations of adult cell types from normal human pancreas

o Identify growth factors, extracellular matrix components, and/or signaling 
molecules that may stimulate proliferation of functional adult beta cells
o Determine the cell surface and extracellular matrix components in the human 
islet involved in cell-cell contact and in the organization of the islet

o Determine the morphology and function of islets following transplantation 
into different locations in appropriate animal models 
o Catalog and explore the function of newly identified proteins specific for 
the beta cell.  For example, determine their subcellular localization, their 
interaction partners, and role in beta cell function in human islets
This Program Announcement will use the NIH Exploratory/Development Research 
Grant (R21) award mechanism
(see https://grants.nih.gov/grants/guide/pa-files/PA-03-107.html).
As an applicant, you will be solely responsible for planning, directing, 
and executing the proposed project.  

Applicants for the R21 must limit their requests to $250,000 direct costs per 
year and are limited to two years. These R21 grants will not be renewable; 
continuation of projects developed under this program will be through the 
regular research grant (R01) program.  

This RFA 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 format.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at 

The NIDDK intends to commit approximately $2,000,000 in FY 2004 to fund 4 to 
5 new grants, and approximately $2,000,000 in FY 2005 to fund 4 to 5 new 
grants in response to this RFA. An applicant may request a project period of 
up to 2 years and a budget for direct costs of up to $250,000 per year. 
Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and duration of 
each award will also vary. Although the financial plans of the NIDDK provide 
support for this program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
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


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.   


We encourage your inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 

o Direct your questions about scientific/research issues to:

Thomas Eggerman, M.D., Ph. D.
Islet Transplantation Program Director
Division of Diabetes, Endocrinology and Metabolism
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 697
Bethesda, MD  20892-5460
Telephone:  (301) 594-8813
FAX:  (301) 480-3503 
E-mail: te39q@nih.gov

Carol Renfrew Haft, Ph.D.
Cell Biology Program Director
Division of Diabetes, Endocrinology and Metabolism
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Bouleveard, Room 605
Bethesda, MD  20892-5460
Telephone:  (301) 594-7689
FAX:  (301) 480-3503 
E-mail: ch84g@nih.gov

o Direct your questions about peer review issues to: 

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email: fc15y@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: dp43b@nih.gov 

Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows NIDDK staff to estimate the potential review workload and 
plan the review.
The letter of intent is to be sent one month prior to the application receipt 
dates listed at the beginning of this document (e. g. October 20, 2003 or 
June 20, 2004).  The letter of intent should be sent to:

Chief, Review Branch 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  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.

SUPLEMENTAL INSTRUCTIONS: All application instructions outlined in the PHS 
398 application kit are to be followed, with the following requirements for 
R21 applications:  

1. R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" 
concepts, with direct costs requested in $25,000 modules, up to the total 
direct costs limit of $250,000 per year. 

2. Although preliminary data are not required for an R21 application, they 
may be included.

3. Sections a-d of the Research Plan of the R21 application may not exceed 
15 pages, including tables and figures.  

4. R21 appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to circumvent 
the page limit for the research plan.  Copies of appendix material will only 
be provided to the primary reviewers of the application and will not be 
reproduced for wider distribution.  The following materials may be included 
in the appendix:

o  Up to five publications, including manuscripts (submitted or accepted for 
publication), abstracts, patents, or other printed materials directly 
relevant to the project.  These may be stapled as sets.

o  Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may be stapled as sets.

o  Original glossy photographs or color images of gels, micrographs, etc., 
provided that a photocopy (may be reduced in size) is also included within the 
15 page limit of items a-d of the research plan.

APPLICATION RECEIPT DATES: Applications submitted in response to this Request 
For Applications will be accepted on November 20, 2003, and July 20, 2004. 
up to $250,000 per year in direct costs 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 
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 

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked. The RFA label is also available at: 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three 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)
At the time of submission, two additional copies of the application and all 
appendices must be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
6707 Democracy Boulevard, Room 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the applicant 
without review. 

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.
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes.  While the 
investigator may still benefit from the previous review, the RFA application 
is not to state explicitly how.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the NIDDK in accordance with the review criteria stated below.  

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 National Diabetes and Digestive and 
Kidney Diseases Advisory Council.


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, 
specific to the objectives of the RFA, 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?  

SPECIAL R21 REVIEW CRITERIA: The R21 exploratory/development grant is a 
mechanism for supporting novel scientific ideas or new model systems, as well 
as for supporting the development of tools and 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 R21 
grant application need not have background material or preliminary 
information as one might normally expect in an R01 application.  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 these R21 

ADDITIONAL REVIEW CRITERIA: Some of the responsive studies may be 
descriptive in nature or hypothesis generating, rather than hypothesis 
driven, and therefore the review criteria for innovation will have reduced 
importance.  In addition, preliminary data, especially data in the human 
islet, is not a requirement.  

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.  Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, 

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.  


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.


Letter of Intent Receipt Date:  October 20, 2003           June 20, 2004
Application Receipt Date:       November 20, 2003          July 20, 2004
Peer Review Date:               March 2004                 October 2004
Council Review:                 May 2004                   February 2005
Earliest Anticipated Start Date:July 2004                  March 2005


Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic 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, 
1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

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 

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 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 RFA 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.

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.

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