DEVELOPMENT OF THE ENDOCRINE PANCREAS 

RELEASE DATE:  August 30, 2002

PA NUMBER: PA-02-161  (Reissued as PA-06-271 for R01s and PA-06-272 for R21s)

EXPIRATION DATE: After October 1, 2005, unless reissued.

National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK)
 (http://www.niddk.nih.gov) 

THIS PA CONTAINS THE FOLLOWING INFORMATION

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 Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE

This program announcement is intended to stimulate the application of 
advances in developmental biology, specifically in developmental 
genetics, embryology, and stem cell biology, to study pancreatic 
development.  Collaborative efforts that link expertise in basic 
developmental biology or stem cell biology and diabetes are strongly 
encouraged.  It is anticipated that this research will ultimately lead 
to a better understanding of the pathways required for the development 
and regeneration of the endocrine pancreas, both in vivo and in vitro. 
The NIH will allow federal funding for research using human embryonic 
stem cells and an NIH registry for human embryonic stem cell lines has 
been established (http://escr.nih.gov).  This PA will support efforts 
in the characterization of these human embryonic cell lines, as well as 
human fetal and adult stem cells as they relate to the specification of 
endoderm and differentiation of pancreatic islet cell types.   This PA 
is intended to intensify investigator-initiated research, to attract 
new investigators to the field, and to encourage interdisciplinary 
approaches to research in this area.

This program announcement replaces PAS 00-015.

RESEARCH OBJECTIVES

Background

Processes fundamental to the development of all organ systems include 
germ layer specification, cell fate determination, pattern formation, 
proliferation, and differentiation.  Inductive signals, including those 
of the TGF beta family and FGF family, are produced by the notochord, 
the tissue adjacent to the endoderm, and are thought to be responsible 
for specifying endoderm.  These signals induce downstream endodermal-
specific transcriptional factors such as the Mix-type homeobox 
proteins, Gata factors, and Sox proteins.  During embryogenesis, 
endoderm-derived organ formation is accomplished through an 
orchestration of signaling pathways that specify the distinct organ 
anlagen.   Signals such as sonic hedgehog must be excluded from the 
developing pancreatic anlagen for proper pancreas development, while 
signals produced by the mesenchyme are necessary for pancreatic 
differentiation into specified cell types. Development of endocrine 
organs involves the "budding morphogenesis" of an epithelial layer in 
order to create a specific organ.  Additionally, developmental signals 
that arise from blood vessels can regulate pancreatic organogenesis.  
Some factors, such as Hex, do not influence specific cell type
decisions but may control competence.  Initiation of bud formation 
requires the transcriptional factor HlxB9 while the pdx1/IDX1 is 
necessary for pancreas development and outgrowth. Genes of the 
Notch/Delta pathway regulate the ability of a cell to initiate 
differentiation in the endocrine pancreas.  For example, ngn3, a key 
component of the Notch pathway is required for the formation of the 
endocrine pancreas.  Cell fate decisions in the endocrine pancreas 
involve a host of transcriptional regulators, which include Pax4, 
Nkx2.2, Nkx 6.1, Pax6, Isl1 and NeuroD.  For the endocrine pancreas, 
this ultimately means differentiation into the cell types responsible 
for production of insulin, glucagon, etc.  TGF alpha/betas and hedgehog 
signaling pathways, in their regulation of the extracellular matrix, 
may be key activators in islet morphogenesis.  Little is known about 
the mechanisms that regulate the migration of islet precursors, but it 
is likely that cell adhesion molecules such as integrins and perhaps 
some of the molecules involved in cell guidance in the nervous system 
could play a role.  

In the last decade, studies in non-vertebrate genetic models of C. 
elegans and Drosophila have provided a wealth of scientific advances in 
the definition of early developmental pathways.  In the next decade, 
the emerging genetic model, zebrafish, can be exploited for dissecting 
events in endoderm development and morphogenesis of the pancreas.  Non-
genetic models such as Xenopus and chick have proven useful in 
identifying and characterizing novel signals and associated components 
of signaling pathways as well as transcriptional regulators in endoderm 
development and organ morphogenesis.  Understanding the regulation of 
cell and tissue-specific gene expression in pancreatic development has 
lead to the generation of useful transgenic mouse models of diabetes.  
Some of these and future mouse models will be useful for determining 
pancreatic cell lineage and for prospectively isolating and 
characterizing stem/progenitor cells from the pancreas.  Public 
databases such http://www.cbil.upenn.edu/EPConDB/index.shtml focused on the 
developing endocrine pancreas will serve as a resource in identifying 
novel genes that play a role in pancreas development and in identifying 
potential cell-specific surface markers at different stages of 
pancreatic development.  Furthermore, the use of cDNA microarrays 
enriched in genes expressed in the developing endocrine pancreas will 
aid in the characterization of pancreatic stem/progenitor cells by 
establishing gene expression profiles and also aid in the phenotypic 
characterization of the growing number of mouse models of diabetes. In 
the future, related resources will be available through the NIDDK-
funded Beta Cell Biology Consortium (http://www.betacell.org).

Type 1 and Type 2 diabetes result from the loss or dysfunction of 
insulin-producing cells of the pancreas. Replacement of these cells, 
through transplantation, could offer lifelong treatment for diabetics.  
However, a major problem in implementing treatment is the lack of 
sufficient islet cell tissue for transplantation. Embryonic stem cells 
and other tissue-specific stem cells could potentially provide a 
limitless source of islet cells for transplantation therapies.  
Experimentation on mouse and human embryonic stem cells has shown that, 
in principle, these cells are capable of giving rise to pancreatic 
islet-like structures that produce insulin under certain culture 
conditions.  Putative stem/progenitor cells have been isolated from 
human pancreatic duct and islet tissue, however further 
characterization of these cell populations is needed.  These studies 
are still in their infancy, and a more fundamental understanding of the 
how to efficiently generate large numbers of functioning pancreatic 
islets from embryonic or tissue-specific stem cells remains a 
challenge. 

Scope and Objectives

o Developmental genetic screens for identifying mutations that affect 
pancreas development.

o Identification of signals, signaling pathway components and 
transcriptional factors that regulate endoderm specification, dorsal 
pancreatic bud formation, and pancreatic fate determination.

o Role of cell-cell interactions, differential cell adhesion, and cell 
motility in morphogenesis of the pancreatic islet.

o Role of extracellular matrix in islet cell morphogenesis.

o Molecular markers for defining all stages of pancreatic development, 
including cell-specific markers of stem/progenitor cells of the 
endocrine pancreas.

o Studies examining endocrine pancreatic cell lineage, including 
alpha, beta, and delta cell fate determination and differentiation.

o Molecular characterization and comparison of human embryonic stem 
cell lines and other human tissue-specific stem/progenitor cells to 
produce endoderm and ultimately differentiated cells of the 
endocrine pancreas.

o Prospective isolation, purification and characterization of 
pancreatic stem/progenitor cells.

o Development of clonogenic assays, both in vitro and in vivo, for 
characterizing stem/progenitor cells of the pancreas.

o Identification of growth conditions required to generate 
differentiated cells of the endocrine pancreas from mammalian 
stem/progenitor cells.

o Use of model systems for the study of regeneration of the endocrine 
pancreas.

o Studies to understand the molecular basis of transdifferentiation of 
gut, liver, and exocrine pancreatic stem/progenitor cells to produce 
pancreatic islets.

o Studies examining the plasticity of hematopoietic, mesenchymal, 
liver, neural and other tissue-specific stem/progenitor cells in the 
formation of pancreatic islets.

MECHANISMS OF SUPPORT

This PA will use the National Institutes of Health (NIH) research 
project grant (R01) and Exploratory/Developmental Research Grant (R21) 
award mechanisms.  The R21 awards are to demonstrate feasibility and to 
obtain preliminary data testing innovative ideas that represent a clear 
departure from ongoing research interests.  These grants are intended 
to: (1) provide initial support for new investigators, (2) allow 
exploration of possible innovative new directions for established 
investigators, and (3) stimulate investigators from other areas to 
limit their expertise to research within the scope of this 
solicitation.  Applicants for the R21 must limit their requests to 
$100,000 direct costs per year and are limited to two years.  These R21 
grants are not renewable, continuation of projects developed under this 
program will be through the regular research grant (R01) program. 

Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.  The total 
project period for an R01 application submitted in response to this PA 
may not exceed 5 years.

This PA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats (see 
http://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.  Otherwise 
follow the instructions for non-modular research grant applications.

ELIGIBLE INSTITUTIONS

You may submit (an) application 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

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

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

Direct your questions about scientific/research issues to:

Sheryl M. Sato, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, Room 6105
6707 Democracy Boulevard
Bethesda, MD 20892-5460
Telephone: (301)594-8811
FAX: (301)480-3503
Email: ss68z@nih.gov

Direct your questions about financial or grants management matters to:

Kathleen Shino
Division of Extramural Activities
2 Democracy Plaza, Room 708
6707 Democracy Boulevard
Bethesda, MD 20892-5456
Telephone: (301) 594-8869
FAX: (301) 594-9523
Email: ks48e@nih.gov

SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001). The PHS 398 is 
available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format. For further assistance contact Grants Info, 
Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov

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

SPECIFIC INSTRUCTIONS FOR R21 APPLICATIONS

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 $100,000 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
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting 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
http://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
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER 
YEAR:  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 
http://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 received by or mailed 
before the receipt dates described at
http://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 
application already reviewed, but such application must include an 
Introduction addressing the previous critique. 

PEER REVIEW PROCESS
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(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 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

REVIEW CRITERIA
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 your 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 your application"s overall score, weighting them 
as appropriate for each application. Your 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, 
you may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

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

(2) APPROACH: Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project? Do you acknowledge potential problem areas and 
consider alternative tactics?

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

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

(5) ENVIRONMENT: Does the scientific environment in which your work 
will be one 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, your
application will also be reviewed with respect to the following:

PROTECTIONS: The adequacy of the proposed protection for humans, 
animals, or the environment, to the extent they may be adversely 
affected by the project proposed in the application.

INCLUSION: The adequacy of 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 included in the section on Federal Citations, below)

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.

AWARD CRITERIA

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

REQUIRED FEDERAL CITATIONS

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research 
components 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: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the 
policy of the NIH that women and members of minority groups and their 
subpopulations 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  of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT 
"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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
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 
differences. 

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS:
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
http://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
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
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at 
http://grants.nih.gov/grants/stem_cells.htm and at 
http://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 review.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The 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
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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.

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
ttp://www.health.gov/healthypeople. 

AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance No. 93.847 and is not subject to
the intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review. Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284 and administered under NIH grants policies described at
http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

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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