DEVELOPMENT OF THE ENDOCRINE PANCREAS

Release Date:  December 1, 1999
 
PA NUMBER:  PAS-00-015

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Child Health and Human Development

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

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.  This PA, with set-asides of funds in FY 
2000-2002, is intended to intensify investigator-initiated research, to 
attract new investigators to the field, and to encourage interdisciplinary 
approaches to research in this area.
 
HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2000," a PHS-
led national activity for setting priority areas.  This PA, Development of 
the Endocrine Pancreas, is related to the priority area of Diabetes.  
Potential applicants may obtain a copy of "Healthy People 2000" at 
http://odphp.osophs.dhhs.gov/pubs/hp2000

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and 
nonprofit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal Government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 
investigators.

MECHANISM 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 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 will 
not be 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.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grants can be 
found at http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE

For FY 2000, $1.5 million will be set aside to fund competing applications 
submitted in response to this PA.  For FY 2001 and 2002, $2.0 million will be 
set aside to fund competing applications in each year.  However, these 
funding levels are dependent upon the receipt of a sufficient number of 
applications of high scientific merit.  The award of grants pursuant to this 
PA is also contingent upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Processes fundamental to the development of all organ systems include germ 
layer specification, cell fate determination, pattern formation, 
proliferation, and differentiation.  In general, the activation of a specific 
developmental pathway is initiated by an extracellular signal.  Signaling 
molecules that are utilized during development are very diverse and include 
members of the transforming growth factor superfamily (TGFs, including bone 
morphogenetic proteins), the epidermal growth factor family (EGFs), the 
fibroblast growth factor family (FGFs), the wingless family (Wnts), sonic 
hedgehog family (shh), Notch-like signals, and cytokines such as interleukin-
3 (IL-3).  Additionally, signaling cascades can be triggered by cell-cell or 
cell-matrix contact (i.e., integrins).  These signaling cascades culminate in 
the temporal and spatial expression of an array of negative and positive 
transcriptional regulators.  Ultimately, the "readout" of these signaling 
events will produce a defined cellular phenotype.  Applying basic knowledge 
of these developmental processes may lead to the rational design of protocols 
to regenerate key endocrine tissues devastated by diseases like diabetes 
mellitus, such as the endocrine pancreas.
	
Preliminary studies on endoderm development show that inductive signals, 
including those of the TGF beta family, can specify endoderm, inducing 
endodermal-specific transcriptional determinants such as Mixer and the Sox 
genes.  Signals produced by the notochord, the tissue adjacent to the 
endoderm, are thought to be responsible for determining pancreatic cell fate.  
Development of endocrine organs involves the "budding morphogenesis" of an 
epithelial layer in order to create a specific organ.  The dorsal pancreatic 
bud expresses a number of transcriptional regulators, including Isl1, 
pdx1/IDX1, nkx2.2, pax 4, pax6 and HNF 3 beta. Many of these transcriptional 
regulators are required for proper development of the endocrine pancreas.  
Signals such as shh must be excluded from the developing pancreatic anlagen 
for proper pancreas development, while signals produced by mesenchyme are 
necessary for pancreatic differentiation into specified cell types.  For the 
endocrine pancreas, this ultimately means differentiation into cell types 
responsible for production of insulin, glucagon, etc. TGF alpha/betas in 
their regulation of the extracellular matrix may be key activators in islet 
morphogenesis.    
	
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. 
BETA2/NeuroD, a basic helix-loop-helix transcription factor involved in 
pancreatic endocrine development was isolated using insulin gene regulation 
as a paradigm.  The study of how cell- and tissue-specific gene expression in 
beta cell development is regulated may lead to the generation of useful 
animal models of diabetes (i.e. conditional knock-outs in the mouse).  The 
combined use of non-mammalian and mammalian developmental model systems will 
play an important role in understanding endoderm development and, in 
particular, the development of the endocrine pancreas.

Type 1 and type 2 diabetes result from the anatomical and functional loss of 
insulin-producing beta cells of the pancreas.  Replacement of these cells 
through regeneration or transplantation could offer lifelong treatment for 
diabetics.  However, a major problem in implementing treatment is the lack of 
sufficient islet cell tissue for transplantation, and a lack of understanding 
of whether and how beta cells regenerate.  Embryonic stem cells and other 
tissue-specific stem cells could potentially provide a limitless source of 
islet cells for transplantation therapies.  Despite major advances in stem 
cell research and in defining specific developmental pathways in neurobiology 
and hematopoiesis, a fundamental understanding of the developmental pathways 
leading to formation of differentiated cells in the endocrine pancreas is 
still in its infancy. 

Scope and Objectives

Investigators with diverse scientific interests are invited to apply their 
expertise in basic research to enhance our fundamental understanding of 
development of the endocrine pancreas.  Examples that illustrate areas to be 
considered within the intent of this solicitation are presented below.  The 
following examples should be considered illustrative and not restrictive, and 
other innovative approaches are encouraged: 

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

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

o The role of cell-cell interactions, differential cell adhesion and cell 
motility in morphogenesis of the pancreas.

o The role of extracellular matrix in islet cell morphogenesis.

o Molecular markers for defining all stages of pancreas 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 Studies exploring the potential use of embryonic stem cells, hematopoietic, 
neural and other stem cells in the formation of differentiated cells of the 
endocrine pancreas.

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

o Generating or using model systems for the study of regeneration of the 
endocrine pancreas.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification is provided that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research.  This new policy results from the NIH Revitalization Act of 
1993 (Section 492B of Public Law 103-43).
 
All investigators proposing research involving human subjects should read the 
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical 
Research," which was published in the Federal Register of March 28, 1994 (FR 
59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 23, No. 
11, March 18, 1994, available on the web at 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH 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 was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators may also obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev. 
4/98) and will be accepted at the standard application deadlines as indicated 
in the application kit.  Application kits are available at most institutional 
offices of sponsored research, or may be obtained from the Division of 
Extramural Outreach and Information Resources, National Institutes of Health, 
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-
435-0714, email: GrantsInfo@nih.gov.

Applicants planning to submit an investigator-initiated new (type 1) 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that he or she must contact NIDDK or 
NICHD program staff before submitting the application, i.e., as plans for the 
study are being developed.  Furthermore, the application must obtain 
agreement from the staff that the NIDDK will accept the application for 
consideration for award.  Finally, the applicant must identify, in a cover 
letter sent with the application, the staff member and Institute or Center 
who agreed to accept assignment of the application.

This policy requires an applicant to obtain agreement for acceptance of both 
any such application and any such subsequent amendment.  Refer to the NIH 
Guide for Grants and Contracts, March 20, 1998 at 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html.

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award. It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers, 
and Institute staff.  The research grant application form PHS 398 (rev. 4/98) 
is to be used in applying for these grants, with the modifications noted 
below.

BUDGET INSTRUCTIONS

Modular R01 Grant applications will request direct costs in $25,000 modules, 
up to a total direct cost request of $250,000 per year.  (Applications that 
request more than $250,000 direct costs in any year must follow the 
traditional PHS 398 application instructions.)  R21 applications will request 
1 or 2 modules of $25,000.  The total direct costs must be requested in 
accordance with the program guidelines and the modifications made to the 
standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative (F&A) costs] for the initial 
budget period.  Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD:  Do not complete Form Page 4 
of the PHS 398. It is not required and will not be accepted with the 
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT:  Do not complete the 
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION:  Prepare a Modular Grant Budget Narrative 
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm
for sample pages.)  At the top of the page, enter the total direct costs 
requested for each year.  This is not a Form page.

o Under Personnel, list key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000.  List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project.  Indicate whether the collaborating institution 
is foreign or domestic.  The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium. 

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH:  The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three 
pages may be used for each person. A sample biographical sketch may be viewed 
at: http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page
- List position(s) and any honors
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years
- List selected peer-reviewed publications, with full citations

o CHECKLIST:  This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the 
type of agreement and the date. All appropriate exclusions must be applied in 
the calculation of the F&A costs for the initial budget period and all future 
budget years.

o The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review.  The program announcement title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked.

Submit the signed, original, single-sided application, including the 
Checklist, along with five signed photocopies and five collated sets of 
appendix materials 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)

The Center for Scientific Review (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 substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public Health 
Service referral guidelines.  Applications will be evaluated for scientific 
and technical merit by an appropriate scientific review group convened in 
accordance with the standard NIH peer review procedures.  As part of the 
initial merit review, all applications will receive a written critique and 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of applications under review, will 
be discussed, assigned a priority score, and 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, reviewer 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.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that 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.

o 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?

o 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?

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

o 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)?

o 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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o Adequacy of plans to include both genders, minorities and their subgroups, 
and children as appropriate for the scientific goals of the research.  Plans 
for the recruitment and retention of subjects will also be evaluated. 

o The reasonableness of the proposed budget and duration to the proposed 
research.

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

o Availability of special opportunities for furthering research programs 
through the use of unusual talent resources, populations, or environmental 
conditions in other countries which are not readily available in the United 
States or which provide augmentation of existing U.S. resources.

AWARD CRITERIA

Applications will compete for available funds within the annual set-aside 
mentioned under FUNDS AVAILABLE.  Beyond the limits of the set-aside 
applications will compete with all other recommended applications assigned to 
the National Institute of Diabetes and Digestive and Kidney Diseases.  The 
following will be considered in making funding decisions:

o Quality of the proposed project as determined by peer review;

o Availability of funds;

o Program priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Sheryl M. Sato, Ph.D.
Division of Diabetes, Endocrinology, and Metabolism
NIDDK
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8811
FAX: (301) 480-3503
E-mail:  satos@extra.niddk.nih.gov

Gilman Grave, M.D.
Center for Research for Mothers and Children
NICHD
6100 Executive Blvd., Room 4B11
Bethesda, MD 20892-7510
Telephone: (301) 496-5593
FAX?301) 480-9791
E-mail: graveg@hd01.nichd.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Ephraim Johnson
Division of Extramural Activities
NIDDK
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8868

E. Douglas Shawver
Grants Management Branch
NICHD
6100 Executive Blvd., Room 8A17
Bethesda, MD 20892-7510
Telephone: (301) 496-1303
FAX?301) 402-0915
E-mail: shawverd@hd01.nichd.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos. 
93.847 and 93.865.  Awards are made under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 
99-158, 42 USC 241 and 285) and administered under NIH grants policies and 
Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.

The NIH strongly encourages all grant and contract recipients to provide a 
smoke-free workplace and promote the non-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 NIH mission to protect and advance the physical and mental health of 
the American people.

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