Full Text DK-93-10


NIH GUIDE, Volume 21, Number 44, December 11, 1992

RFA:  DK-93-10

P.T. 34

  Gene Cloning 
  Genetic Manipulation 
  Gene Products 

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  February 18, 1993
Application Receipt Date:  March 17, 1993


The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and the American Diabetes Association (ADA) invite
investigator-initiated research grant applications to identify specific
genes responsible for non-insulin dependent diabetes mellitus (NIDDM)
in humans.  It is anticipated that this identification will require an
interdisciplinary approach to develop and utilize strategies that will
elucidate genes responsible for NIDDM using appropriate family

Applications will be submitted to the National Institutes of Health
(NIH) and will be reviewed by NIH according to the usual NIH peer
review procedures.  Applications judged meritorious and designated for
funding will be supported partially by the NIDDK and partially by the
ADA through the issuance of coordinated but separate awards by the two
funding organizations.  In order to facilitate the coordination of the
NIDDK and the ADA, applicants are requested to provide the NIDDK
authorization to allow the NIDDK to provide a copy of their letter of
intent, application, NIH-prepared summary statement of the initial
review, and yearly progress reports (if the application is funded) to
the ADA.  Applicants wishing to be considered for funding only by the
NIDDK should so indicate in their letter of authorization.  Under these
latter circumstances, no information pertaining to their application
will be shared with the ADA.


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 Request
for Applications (RFA), Human Genes for Non-Insulin Dependent Diabetes
Mellitus, 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
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).


Applications for research grants may be made by public and private,
foreign and domestic, for-profit and non-profit organizations, such as
universities, colleges, hospitals and laboratories, units or State and
local governments, and authorized units of the Federal Government.
Women and minority investigators are encouraged to apply.


This RFA will use the NIH research project grant (R01).  Responsibility
for the planning, direction, and execution of the proposed project will
be solely that of the applicant.  The total project period for an
application submitted in response to the present RFA may not exceed
five years.  The anticipated award date is September 30, 1993.

For the purpose of cost-containment, requested direct costs must not
exceed $160,000 per year for any single application.  Applications
exceeding this limit will not be reviewed as part of this RFA.  The
average award made by the NIDDK is expected to be approximately
$200,000 in total costs.

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


Highly meritorious applications in response to this solicitation will
be partially funded by the NIDDK and partially funded by the ADA if
permission is given by the applicant.

The NIDDK will commit up to $2 million for first-year expenses and
additional funds for approved expenses in subsequent years for up to
five years to fund applications submitted in response to this RFA.  The
ADA anticipates support of up to 20 percent of recommended direct costs
for each funded application per year.  The NIDDK and the ADA plan to
make approximately 10 to 12 awards in FY 1993 contingent on the receipt
of highly meritorious applications in response to this solicitation.
With respect to post-award administration, the current policies and
requirements that govern the research grant programs of the NIH will
prevail for awards made by the NIDDK.  Applicants should note that
funds from the ADA will be subject to the indirect cost policy and
post-award administration policies of the ADA.  The award of grants
pursuant to this RFA is contingent on the availability of funds for
this purpose.



The term "diabetes" encompasses a number of different diseases, and
hence, a number of different genes may be involved.  Because of the
potential for complex interplay between several genes, novel approaches
may be necessary to ascertain the genes involved in the etiology of
diabetes.  The NIDDK recognizes this area as a high priority for
research and has taken steps to stimulate research in genetics and
molecular biology.  In addition, the National Diabetes Advisory Board,
in its "Long-Range Plan to Combat Diabetes, 1987," made several
recommendations to the NIDDK directed at increasing progress in this
area, including an increased emphasis on interdisciplinary research
collaboration.  In 1990, the NIDDK convened a scientific workshop to
address opportunities in the search for the diabetes genes.  The
participants analyzed the current state of knowledge and endorsed a
multifaceted and concerted effort to discover the genetic basis of
diabetes and its complications.

The NIDDK is coordinating efforts with the ADA to expeditiously and
efficiently achieve the goal of both organizations: identify genes
responsible for NIDDM.  Toward this end, the ADA has recently embarked
on the development of family pedigrees and the acquisition of genetic
resources to aid in the elucidation of human genes responsible for

The last decade has witnessed an expansion in knowledge and scientific
methods allowing the isolation of genes responsible for a few but
growing number of severe human diseases, such as Duchenne muscular
dystrophy and Huntington's disease.  Most recently, a five-year effort
has culminated in the cloning and sequencing of the gene responsible
for cystic fibrosis.  This achievement has had a dramatic effect on
research into the cause and cure for cystic fibrosis.  Similar
scientific approaches are being directed toward the search for the
diabetes genes.

NIDDM affects approximately 13 million Americans.  It is the
predominant form of the disease and severely impacts upon U.S. minority
populations.  This clustering of prevalence among ethnic/racial groups
along with twin and family studies and animal models points to the
genetic nature of this disease.  Several genetic markers have been
described as being associated with a rare form of NIDDM called Maturity
Onset Diabetes of the Young (MODY) that shows autosomal dominant
inheritance.  One of these genetic markers is the gene for glucokinase,
a key enzyme of glucose homeostasis found in the insulin-secreting beta
cell of the pancreas and in the liver.  This is the first evidence that
a gene involved in glucose metabolism could be implicated in the
pathogenesis of NIDDM.  A variety of other genes may be related to the
long-term complications suffered by those with all forms of diabetes.
It will be worthwhile to apply a wide array of molecular biological
techniques to explore genes related to insulin secretion, insulin
action and key metabolic processes that regulate the body's metabolism.

It is important to identify specific genetic markers/elements that are
relevant to diabetes and its complications.  These markers can take the
form of genetic-susceptibility markers identifying the presence of
specific genetic loci that predispose an individual to the disease
and/or genetic mutations in key metabolic elements involved in the
pathogenesis of NIDDM.


Through this solicitation, the NIDDK and the ADA intend to stimulate
investigator-initiated research designed to develop and utilize new
molecular genetic strategies to provide a better understanding of the
major genes involved in NIDDM in humans.  To achieve this objective,
appropriate family pedigrees may need to be collected as a prerequisite
for the identification or for the verification of specific gene
involvement.  Since a large number of families may need to be
recruited, accumulation of these families must be included within the
framework of the proposed research plan.  Utilization of existing
sources of genetic material is encouraged.  For example, the ADA is
developing a repository of data, DNA, and cell lines of family
pedigrees with NIDDM.  This repository will be completed by the spring
of 1995 but data and cell samples will likely become available much

It is anticipated that these results will elucidate mechanisms involved
in disease onset, thus enabling the development of specific
intervention therapies and the identification of individuals at risk
for the development of NIDDM.  Relevant research topics listed below
are examples and should not be construed as required or limiting.
Responsive applications to this solicitation include:

o  development of gene mapping strategies for the specific
identification and localization of genes for NIDDM

o  utilization of subtractive hybridization techniques to identify
pathophysiologic processes in NIDDM

o  employment of highly informative polymorphic markers such as
variable number repeat polymorphisms or microsatellite markers to
evaluate relevant family pedigrees.

Applications must propose the testing of an hypothesis rather than the
establishment of, for example, a genetic resource.


Upon initiation of this program, the NIDDK and the ADA will sponsor
periodic meetings to encourage exchange of information among
investigators, to foster collaborative efforts between program
grantees, and to identify resources that would enhance the productivity
of grantees.  For this purpose, requests for travel funds for a one day
meeting each year, probably to be held in the Washington, DC
metropolitan area, must be included in the budget section of the
application.  It is anticipated that the first meeting will be held
soon after the award of grants in order to discuss and establish the
nature and extent of possible collaboration among the group of

Applicants should also include a statement in their applications
indicating their willingness to participate in such meetings.

Letter of Authorization

Each applicant must submit a brief statement to the NIDDK indicating
whether or not they wish their application to be considered for
coordinated funding by the ADA.  Although applicants may request that
their applications be considered only by the NIDDK and not by the ADA,
it is necessary that the record indicate the applicant's consideration
of this opportunity.  For each applicant who wishes to have the ADA
consider their application for coordinated funding, all materials
relating to the application will be promptly forwarded to that
organization by the NIDDK, and the summary statement for the
application will be shared with the ADA at the time of their
availability.  The NIDDK will provide no information to the ADA, nor
any other non-governmental agency, related to applications from any
applicant who requests that the ADA not consider their application.
Letters of authorization should be prepared by the Principal
Investigator and co-signed by the official signing for the applicant
organization.  This must be submitted as a cover letter accompanying
the application.

Whether or not an applicant wishes to be considered for coordinated
funding by the ADA will not effect the funding decisions of the NIDDK.



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis should be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to apply
to males and females of all ages.  If women or minorities are excluded
or inadequately represented in clinical research, particularly in
proposed population-based studies, a clear compelling rationale should
be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 (rev. 9/91) in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.  Applicants are urged to assess carefully the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventative strategies), diagnosis, or treatment or diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.


Potential applicants are strongly encouraged to submit a letter of
intent by February 18, 1993.  The letter of intent is to include:  (1)
names of the Principal Investigator/program director and principal
collaborators, (2) descriptive title of the potential application, (3)
identification of the organization(s) involved, and (4) 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 subsequent applications, the information
that it contains is helpful in planning for the review of applications.
It allows NIDDK staff to estimate the potential review workload and to
avoid conflict of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
5333 Westbard Avenue
Bethesda, MD  20892


Applications are to be submitted on form PHS 398 (rev. 9/91), that is
available from an applicant institution's office of sponsored research
and from the Office of Grants Inquiries, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone (301) 496-7441.  Use the conventional format for
research project grant applications.  To identify the application as a
response to this RFA check "yes" on item 2a of page one of the
application and enter the title "Human Genes for NIDDM" and the RFA
number DK-93-10.

The RFA label included in the PHS 398 application package must be
affixed to the face page to assist in the processing of the
application.  Failure to use this label could result in the delayed
processing of the application such that it may not reach the review
committee in time for review.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center of Research Resources
may wish to identify the Center as a resource for conducting the
proposed research.  If so, a letter of agreement from the GCRC Program
Director should be included in the application material.

Applications must be received by March 17, 1993.  If an application is
received after that date, it will be returned to the applicant without
review.  The original, including the Checklist, and three signed
photocopies of the application must be submitted in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must be sent under separate cover to:

Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
5333 Westbard Avenue
Bethesda, MD  20892

The Division of Research Grants (DRG) will not accept any application
in response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  The DRG 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.


Upon receipt, applications will be reviewed by DRG staff for
completeness and by NIDDK staff for responsiveness.  Incomplete
applications will be returned to the applicant without further
consideration.  If the application is not responsive to the RFA, NIDDK
staff will contact the applicant to determine whether to return the
application to the applicant or submit it for review in competition
with unsolicited applications at the next review cycle.

Applications may be triaged by an NIDDK peer review group on the basis
of relative competitiveness.  The NIH will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are complete
and responsive will be evaluated in accordance with the criteria stated
below for scientific/technical merit by an appropriate peer review
group convened by the NIDDK.  The second level of review will be
provided by the National Diabetes and Digestive and Kidney Diseases
Advisory Council.

Applications in response to this RFA will be reviewed using the usual
NIH peer review procedures.  The factors to be considered in the
evaluation of scientific merit of each application will be those used
in the review of traditional research project grant applications,
including the novelty, originality, and feasibility of the approach;
the training, experience, and research competence of the
investigator(s); the adequacy of the experimental design; the
suitability of the facilities; the appropriateness of the requested
budget to the work proposed; and the adherence, whenever appropriate,
to NIH guidelines concerning clinical research involving minorities and


The anticipated date of award is September 30, 1993.  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  Scientific interrelationships among the proposed projects.


Written and telephone 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.
Executive Director, Diabetes Research Program
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 622
Bethesda, MD  20892
Telephone:  (301) 496-7731

Direct inquiries regarding fiscal matters to:

Betty E. Bailey
Grants Management Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 496-7467


Letter of Intent:               February 18, 1993
Application Receipt Date:       March 17, 1993
Initial Review:                 June/July 1993
NIDDK Advisory Council Review:  September 1993
Anticipated Award Date:         September 30, 1993


This program is described in the Catalog of Federal Domestic Assistance
No. 93.847, Diabetes, Endocrinology and Metabolism Research.  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.


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