THE CELL BIOLOGY OF THE PANCREATIC BETA CELL

NIH GUIDE, Volume 26, Number 34, October 10, 1997

RFA:  DK-98-003

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:  March 19, 1998

PURPOSE

The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) invites investigator-initiated research grant
applications to elucidate the pathways and factors responsible for
the development and maintenance of beta cells in the pancreas. 
Current evidence suggests that the endocrine pancreas is derived
from progenitor cells in the ducts of the exocrine portion of the
pancreas.  An expanded knowledge of the precise location and nature
of these putative progenitor cells, the factor(s) responsible for
differentiation into endocrine cells, the lineage dependent factors
responsible for development of alpha, beta and delta cells,  the
trans-acting factors which subsequently regulate expression of the
genes for the hormones themselves, and the local growth factors
which comprise the milieu of the endocrine islet is crucial to the
development of strategies for islet and/or B cell regeneration.

This solicitation is intended to stimulate the application of
advances in cell biology and molecular biology to the study of the
cell biology of the pancreatic beta cell.  Collaborative efforts
that link expertise in cell biology to expertise in diabetes are
strongly encouraged.  Also, two-year pilot and feasibility
applications are available within this solicitation.  It is
anticipated that results obtained by studies supported by this
solicitation will aid in the development of improved therapies for
the treatment of diabetes mellitus.

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, The Cell Biology of Pancreatic Beta Cells, 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 and foreign, 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 First Independent
Research Support and Transition (FIRST) (R29) awards. 
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 research project
grant (R01) award, the FIRST (R29) award, or the
exploratory/developmental award (R21).  The R21 awards are to
demonstrate feasibility and to obtain preliminary data under
circumstances of strong rational. Responsibility for the planning,
direction, and execution of the proposed project will be solely
that of the applicant.  Awards will be administered under Public
Health Service (PHS) grants policy as stated in the PHS Grants
Policy Statement.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for
conducting the proposed research.  If so, a letter of agreement
from either the GCRC program director or principal investigator
should be included with the application.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all
investigator-initiated applications and be reviewed according to
the customary peer review procedures.  The total requested project
period for an application submitted in response to this RFA may not
exceed five years.  A maximum of three years can be requested for
foreign awards.  Applicants for the R01 mechanism are encouraged to
limit their request to $160,000 in direct costs for the initial
budget period unless there is appropriate justification for an
expanded scope that must not exceed a first year limit of $250,000
direct costs.  Applicants for the R21 must limit their requests to
$100,000 direct costs per year and are limited to 2 years. 
Applicants for the R29 are limited to the National Institute of
Health's guidelines for this award.  Budget escalations in future
years should be limited to 3% of non-recurring costs.  The
anticipated award date is September 30, 1998.

FUNDS AVAILABLE

For FY 1998, $4 million will be committed to fund applications
submitted in response to this RFA.  It is anticipated that 12 to 16
awards will be made.  However, this funding level is dependent upon
the receipt of a sufficient number of applications of high
scientific merit.  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

Diabetes Mellitus affects approximately 16 million people in the
United States.  Individuals with Type 1 diabetes mellitus have lost
their ability to produce insulin due to the immune destruction of
their pancreatic beta cells, which secrete insulin.  Individuals
with Type 2 diabetes mellitus have lost their ability to
over-produce insulin to maintain euglycemia in the presence of
insulin resistance.  Thus, both major forms of diabetes mellitus
demonstrate a loss of sufficient insulin production by the beta
cell.

The results of the Diabetes Control and Complications Trial
indicate that maintenance of near normal glycemic levels can reduce
and delay the onset of the devastating complications of diabetes. 
Therefore, establishing methods of achieving and maintaining
euglycemia will have enormous implications for the health and
quality of life of individuals with diabetes.  To this end,
researchers have tried to develop cellular approaches to insulin
replacement.  These have included replacement of beta cells (islet
transplantation) or utilization of another cell to produce insulin
in response to glucose (bioengineered beta cells).  To date these
efforts have yielded limited success in large part due to our lack
of knowledge of the origins, development and regenerative capacity
of beta cells.  The present solicitation seeks to foster research
in these areas that can be applied to improved therapies in the
future.

SCOPE AND OBJECTIVES

It is thought that the endocrine pancreas is derived from stem
cells in the ducts of the exocrine portion of the pancreas. 
However, there is a paucity of information on the inductive signals
that control the development of the pancreas and the generation of
the individual differentiated cell types.  Progress has been made
on the identification of transcription factors involved in
pancreatic development and understanding the potential role of
certain transcription factors in the impaired insulin production
and reduced beta-cell mass manifested in Type 2 diabetes mellitus.

Spatial identity and patterning in the differentiation of tissues
during embryonic development is regulated by the interplay between
homeobox (Hox) genes and other hormones, local growth factors, and
cytokines. Patterning in complex endocrine organs, such as the
anterior pituitary involves key developmentally expressed signaling
genes including the POU domain proteins.  More recently, evidence
has accumulated to suggest that development of the
well-differentiated cells of the endocrine pancreas also involve
developmentally expressed genes.  For example, ISL1, a
LIM-homeodomain protein capable of interaction with an insulin gene
cis-element, appears to be required in pancreatic endodermal cells
for the generation of endocrine cells, and IDX-1, or PDX-1, appears
to be responsible for the initial differentiation of precursor
cells in the primitive pancreas into endocrine cells.  Further
expression of other cis- and trans-acting factors appears to
subsequently regulate the expression of genes, which express
somatostatin in delta cells, glucagon in alpha cells, and insulin
in beta cells.  Indeed, a human mutation in such a gene results in
pancreatic agenesis.

The scope of the present solicitation includes the acquisition of
knowledge of the precise location, nature, and markers for these
putative stem cells, the factor(s) responsible for differentiation
into endocrine cells, the lineage dependent factors responsible for
development of alpha, beta, and delta cells, the trans-acting
factors which subsequently regulate expression of the genes for the
hormones, themselves, the local growth factors which comprise the
milieu of the endocrine islet, and growth factors for the
propagation of beta cells or their precursors in vitro.  This
knowledge is crucial to the development of strategies for islet
and/or beta cell regeneration.  Such new understanding would also
foster longer-term approaches to gene therapy for diabetes.

Relevant topics listed below are examples and should not be
construed as required or limiting.

o  Determine the location and identity of the stem cells, which
differentiate into cells of the endocrine pancreas

o  Establish cellular markers for isolating lineages of pancreatic
stem cells

o  Identify the factor or factors which provide the signal for the
earliest differentiation of pancreatic endocrine cells and which
subsequently regulate patterning in the endocrine pancreas

o  Identify the factors and/or systemic hormones/local growth
factors, which regulate the growth and development of the cellular
subpopulations of the endocrine pancreas

o  Determine the trans-acting factors that determine the mature
cell phenotype in the separate cell populations of the endocrine
pancreas, including regulation of hormone expression

o  Develop approaches that can be used to identify and regenerate
specific populations of cells within the pancreatic islets

o  Identify the sources and nature of the inductive signals that
control pancreas morphogenesis and cytodifferentiation

o  Study the mechanisms involved in beta cell growth during
pregnancy

o  Examine the possibility of beta cell neogenesis in pathological
states in man, e.g. chronic pancreatitis, obesity, type 1 and type
2 diabetes mellitus

o  Identify syndromes affecting the endocrine pancreas in order to
identify the involved genes

o  Identify key events and molecules in the switch between beta
cell clonal expansion and terminal differentiation

o  Identify factors that maintain terminal differentiation

o  Explain the mechanism of "glucose toxicity" in the beta cell
and/or develop approaches to prevent it

o  Clarify the molecular mechanisms involved in apoptosis of the
beta cell and the means of intervening in this process

o  Elucidate the role of cell-cell interactions within the islet to
explain the differences between isolated beta cells and islets

o  Ascertain the involvement of paracrine factors and/or adhesion
molecules in beta cell growth and differentiation

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.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 19, 1998,
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. 5/95) 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,
MSC-7910, Bethesda, MD 20892-7910, telephone 301-435-0714, email:
asknih@od.nih.gov.

The RFA label available in the PHS 398 (rev. 5/95) 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 (formerly DRG)
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

FIRST (R29) award applications must include at least three sealed
letter of reference attached to the face page of the original
application.  FIRST (R29) award applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.

Applications must be received by March 19, 1998.  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 in accordance with 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 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

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 and minorities and
their subgroups as appropriate for the scientific goals of the
research.  Plans for the recruitment and retention of subjects will
also be evaluated.

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

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

AWARD CRITERIA

The anticipated date of award is September 30, 1998.

The factors that will be used to make award decisions include:

o  scientific and technical merit as determined by peer review,

o  availability of funds, and

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:

Joan T. Harmon, Ph.D.
Chief, Diabetes Research Section, DPB, DDEMD
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 5AN-18G - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8808
FAX:  (301) 480-3503
Email:  Joan_Harmon@NIH.GOV

Direct inquiries regarding fiscal and administrative matters to:

Nancy C. Dixon
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8854
FAX: (301) 480-4237
Email:  dixonn@extra.niddk.nih.gov

Schedule

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:       March 19, 1998
Initial Review:                 June/July 1998
Second Level Review:            September 1998
Anticipated Date of Award:      September 30, 1998

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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