FUNCTIONAL GENOMICS OF THE DEVELOPING ENDOCRINE PANCREAS

Release Date:  December 4, 1998

RFA:  DK-99-007

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  February 10, 1999
Application Receipt Date:  March 10, 1999

PURPOSE

The development of type 1 diabetes is characterized by a progressive autoimmune
destruction of pancreatic beta cells resulting in loss of insulin production. 
Replacement of beta cell function through transplantation or regeneration of beta
cells could provide a major breakthrough in the treatment of diabetes.  However,
the lack of sufficient tissue is a major obstacle to the widespread use of
transplantation and an incomplete understanding of the development and
differentiation of the pancreatic islet reduces the likelihood of successful
regeneration of beta cells either in vitro or in vivo.  To accelerate progress
toward identification of pleuripotential stem cells and factors which regulate
development and differentiation of beta cells the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK) invites investigator-initiated
Resource-Related Research Projects (R24) to establish a pilot functional genomics
resource in diabetes.  This grant award mechanism would support production and
sequencing of expression cDNA libraries based on multiple stages of pancreatic
development.  In addition, this resource would provide bioinformatics links to
existing NIH-supported genomics databases and make pancreatic cDNA libraries
available as microarrays to be used by researchers for gene discovery and
functional investigations in both normal and diabetic pancreas.

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 RFA, Functional Genomics of the
Developing Endocrine Pancreas, is related to the priority area of diabetes and
chronic disabling conditions.  Potential applicants may obtain a copy of "Healthy
People 2000" (Full Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock
No. 017-001-00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone: 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and nonprofit organizations,
public or private, such as universities, colleges, hospitals, laboratories, units
of State and local governments, and eligible agencies of the Federal Government. 
Foreign institutions are not eligible for resource-related research project (R24)
grants.  Racial/ethnic minority individuals, women, and persons with disabilities
are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

Support of this program will be through the NIH grant-in-aid resource-related
research project grant (R24) award.  Responsibility for the planning, direction,
and execution of the proposed project will be solely that of the applicant. 
Awards will be administered under PHS grants policy as stated in the PHS Grants
Policy Statement.

This RFA is a one-time solicitation.  However, if there is sufficient continuing
program need, NIDDK will invite recipients of awards under this RFA to submit
competing continuation applications for review as described in REVIEW
CONSIDERATIONS.  The total requested project period for an application submitted
in response to this RFA may not exceed 3 years.  The maximum dollar request is
limited to $500,000 in direct costs for the initial budget period and $1.5
million in direct costs for the entire project period exclusive of equipment. 
The anticipated award date is September 30, 1999.

FUNDS AVAILABLE

For FY 1999, $1.5M will be committed to fund applications submitted in response
to this RFA.  It is anticipated that one to two awards will be made; however,
this funding level is dependent upon the receipt of a sufficient number of
applications of high scientific merit.  Proposed funding levels are subject to
change due to budgetary, administrative and/or scientific considerations, and are
dependent upon the receipt of a sufficient number of applications of high
scientific merit.  It is expected that major equipment costs will be incorporated
in the first year budget, and that subsequent year budgets should be related to
the anticipated level of library production and sequencing.  Although this
program is provided for in the financial plans of the NIDDK, the award of grants
pursuant to this RFA is also contingent upon the availability of funds for this
purpose.

RESEARCH OBJECTIVES

Background

On September 4-5, 1997, the NIH sponsored a conference, "Diabetes Mellitus:
Challenges and Opportunities." focused on scientific opportunities and directions
that a broad interdisciplinary approach could bring to diabetes research.  Led
by invited, internationally recognized experts in diabetes research, this
conference involved all NIH institutes having a scientific interest in diabetes. 
A primary recommendation of that group was the application of cDNA microarray
technology to the problem of type 1 diabetes.  Over time a general outline of the
morphological events involved in the development of the endocrine pancreas has
emerged.  Signals from adjacent tissues, including the notochord and the
mesenchyme, play an important role in pancreatic islet development and key
mediators of these inductive signals are now being elucidated.  Recent results
have increased our understanding of how the genes required for normal function
of the beta cell are activated.  This work has included the detailed knowledge
of insulin and glucokinase gene regulation and the insights into the role that
a series of tissue-specific transcriptional activators, the HNFs, play in the
regulation of genes involved in glucose sensing.  Additional findings have
identified transcription factor genes involved in the formation and the
maturation of the pancreas and islets.  These factors include IPF1, which is
required for formation of the entire pancreas, and isl1, neuroD1/BETA2 and pax
and nkx genes, which are involved in the formation, expansion and maturation of
islet cells.  Finally, growth factors have been identified that control the
growth and regeneration of islet cells.  These results form the foundation for
expanding research efforts to understand development of the endocrine pancreas
and offer the potential to stimulate regrowth of beta cells in patients with
diabetes.  However, a number of gaps still remain in our understanding of
pancreatic development.  The developmental triggers which establish the
pancreatic beta cell lineage and the inductive signals which control progression
to differentiated beta cells have not been elucidated. Recent advances in DNA
technologies including microarray construction, sequencing speed and fidelity,
and library construction increase the likelihood of discovering many of the genes
that regulate development of the endocrine pancreas.  In addition, the
identification of beta cell specific genes should provide a powerful tool to look
at altered function during the progression of type 1 diabetes.

The National Cancer Institute (NCI) has established the Cancer Genome Anatomy
Project to accelerate the pace of discovery of genes involved tumor progression
and to attempt to harness the vast wealth of sequence data emanating from the
Human Genome Project.  CGAP has become a national network of labs orchestrated
by NCI staff to both discover new cancer genes and elucidate characteristic
patterns of gene expression in normal and malignant tissues which potentially
could be useful in diagnosis and treatment of many cancers.  The bioinformatics
system which has been developed for CGAP ensures that all of the data generated
by this project is available to researchers worldwide soon after it is generated
in the laboratory.  One logical extension of this project, that is, the
development of tools which can use this data in laboratory investigations or
clinical diagnosis is relatively undeveloped.  The current RFA is designed to
stimulate investigations into the application of microarray and detection
technologies to the problem of diabetes through generation of pancreatic cDNA
libraries, sequencing, and construction of microarrays to be used by the general
research community.

Objectives and Scope

This RFA is intended to support the cost-effective generation of arrays of genes
involved in development and differentiation of the mammalian endocrine pancreas.
Since many of these factors may be expressed at very low levels at key stages in
development, strategies should be proposed to increase the representation of low
abundance transcripts in the cDNA libraries and to decrease the redundant
sequencing of overrepresented or known genes.  Applicants may also propose
selection strategies which can be used to determine key regulatory factors in
beta cell development and to develop strategies for regeneration either in vivo
or in vitro of beta cells as a potential therapy for type 1 diabetes.  Other
tissues relevant to diabetes may be included in the proposal, but cannot supplant
the primary objective to focus on developing pancreas.  Experiments focused on
determination of the validity and reliability of pancreatic gene microarrays as
well as their utility in diabetes research may be proposed as well.  A major
objective of this RFA is to disseminate both sequence data and research reagents
to the research community as rapidly as possible.  Therefore, applicants should
exploit existing microarray technologies, which are readily available to the
research community, or propose alternative technologies including plans to make
them widely available to researchers.  A schedule for rapid disposition of
sequences into public databases such as GenBank should be proposed.  A strategy
for developing and maintaining a distinct bioinformatics system for diabetes
related genes may be proposed as an additional resource for researchers.

SPECIAL REQUIREMENTS

Data and Resource Dissemination

The sharing of materials and data in a timely manner has been an essential
element in the rapid progress that has been made in genome research.  Public
Health Service (PHS) policy requires that investigators make the results and
accomplishments of funded activities publicly available.  The advisors to the NIH
and the DOE genome programs have encouraged more rapid sharing, and this has
become the norm in the genome community.  NIDDK encourages applicants who respond
to this RFA to develop and propose specific plans for sharing data and materials
generated through the resource-related research project grant.  It is anticipated
that data obtained, upon sequence validation should be placed in a public
database.  For example, the National Center for Biotechnology Information,
National Library of Medicine (NCBI, NLM) has already in place a database that
contains organized sequence data from libraries produced through the Cancer
Genome Anatomy Project.  Applicants need to describe plans for dissemination of
their sequence data, and the compatibility of their database with other public
databases.

Where appropriate, awardees may work with the private sector in making the
arrayed libraries available to the larger biomedical research community at a
reasonable cost.  The plans proposed for sharing and data release will be
reviewed for adequacy by reviewers as well as NIDDK staff prior to award and will
be considered as a criterion for award.  Funds to defray the costs of submitting
data and distribution of reagents may be included in the application.  Such
requests must be adequately justified.

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
sub-populations 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
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 have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513), and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

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:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by February 10, 1999, a letter of
intent that includes a descriptive title of the proposed research; the name,
address, and telephone number of the Principal Investigator; the identities of
other key personnel and participating institutions; and the number and title of
the RFA in response to which the application may be submitted.

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 avoid conflict
of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and may be obtained from the Division of Extramural Outreach
and Information Resources, National Institutes of Health, 6701 Rockledge Drive,
Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email:
GrantsInfo@nih.gov or electronically at https://grants.nih.gov/grants/forms.htm.

The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application.  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.

Submit a signed, typewritten original of the application, including the
Checklist, plus 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 time of submission, two additional copies of the application must be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD 20892-6600

Applications must be received by March 10, 1999.  If an application is received
after that date, it will be returned to the applicant without review.  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.  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 previously
reviewed, but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

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
NIDDK in accordance with NIH peer review procedures.  All applications will be
judged on the basis of the scientific merit of the proposed project and the
documented ability of the investigators to meet the RESEARCH OBJECTIVES of the
RFA.  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 will be discussed, assigned a priority
score, and receive a second level review by the National Diabetes and Digestive
and Kidney Diseases Advisory Council.

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 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?

o  Appropriateness of the proposed budget and duration in relation to the
proposed research.

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 initial review group will also examine the provisions for the protection
of human and animal subjects, and the safety of the research environment.

Additional Review Criteria Specific for this RFA:

o  The feasibility and merit of the strategy for increasing representation of
rare transcripts.

o  Plans to distribute forthcoming resources in a timely manner, preferably with
track-record of willingness to release data and reagents.

AWARD CRITERIA

The anticipated date of award is September 30, 1999.  The factors that will be
used to make award decisions include:

o  scientific and technical merit as determined by peer review
o  provision for rapid dissemination of results to the research community,
o  availability of funds
o  programmatic priorities

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Philip F. Smith, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8816
FAX: (301) 480-3503
Email: ps56z@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Kieran Kelley
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-0417
FAX: (301) 480-3504
Email: kk27g@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.847.  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 PHS 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 PHS 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 PHS mission to
protect and advance the physical and mental health of the American people.

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