Full Text DK-92-14


NIH GUIDE, Volume 21, Number 10, March 13, 1992

RFA:  DK-92-14

P.T. 34

  Disease Model 

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  June 18, 1992
Application Receipt Date:  July 22, 1992


The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invites investigator-initiated research grant applications to
identify specific genes responsible for insulin dependent diabetes
mellitus (IDDM) in humans.  It is anticipated that this identification
will require an interdisciplinary approach to develop and utilize
strategies that will elucidate genes responsible for IDDM using
appropriate familial pedigrees.  This solicitation intends to support
the efforts of several independent investigators, working in a
collaborative manner to acquire sufficient genetic material, achieve
the mutual objectives, and efficiently integrate and analyze the
results obtained.


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), Genes Responsible for 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 of State and
local governments, and authorized units of the Federal Government.
Women and minority investigators are encouraged to apply.


The mechanism of support for this program will be the
research project grant (R01).  The
regulations (Code of Federal Regulation, Title 42, Part
52 and, as applicable to State and local governments,
Title 45, Part 74) and policies that govern the research
grant programs of the National Institutes of Health will
prevail.  This RFA is a one-time solicitation.  Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant.  The total project period for
applications submitted in response to the present RFA may not exceed
five years.  The anticipated award date will be April 1, 1993.

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 NIH peer review


Up to $1 million for first-year expenses, and additional approved
expenses for up to five years, will be committed by the NIDDK to fund
applications submitted in response to this RFA.  The NIDDK plans to
make approximately five awards in FY 1993 contingent on the receipt of
highly meritorious applications in response to this solicitation.  In
order to adhere to prudent principles of cost-containment, requested
direct costs may not exceed $160,000 for any single application.  With
respect to post-award administration, the current policies and
requirements that govern the research grant programs of the NIH will
prevail.  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 increasing the 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 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.

There has already been progress in the search for the diabetes genes.
Within the last three years, a discovery has uncovered a diabetes
susceptibility gene in IDDM, which affects between 500,000 and 750,000
children and young people in the United States.  This gene appears to
be necessary, but not completely sufficient, to cause the disease.  In
animal models there is a suggestion that additional genes are involved,
but as yet, no other gene has been identified in humans.  There is a
need to search for these other contributing genes in IDDM.

The clinical manifestations of IDDM are the culmination of a
destructive immune process that has gone on silently for years.  By the
time the patient's sickness occurs, it is generally too late to prevent
or reverse the damage.  Therefore, it is important to find markers for
the process at an earlier stage.  These markers can take the form of
genetic-susceptibility markers, identifying the presence of specific
genetic loci, and/or immunological markers, identifying an early
manifestation of the autoimmune process.

While this RFA is designed to identify genes associated with IDDM, the
NIDDK anticipates a future RFA specifically focusing efforts on the
identification of genes involved with non-insulin dependent diabetes


The objective of this RFA is to stimulate investigator-initiated
research grant applications designed to develop and utilize new
molecular genetic strategies to provide a better understanding of the
major human genes involved in IDDM.  To achieve this objective,
appropriate family pedigrees may have 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 collaboration among researchers is
encouraged.  The degree of this collaboration may range from sharing
appropriate family pedigrees or genetic material to devising a joint
plan that divides the studies among the collaborating laboratories and
specifies a central laboratory responsible for such activities as
coordinating acquisition of genetic material, data analysis, and
manuscript preparation.

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

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

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

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 a hypothesis rather than the
establishment of, for example, a genetic resource.


Upon initiation of this program, the NIDDK will sponsor periodic
meetings to encourage exchange of information among investigators,
foster collaborative efforts between program grantees, and 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 Chicago, IL, should be included in the budget
section of the application.

Applicants should also include a statement in the application
indicating a willingness to participate in such meetings and to
cooperate with other researchers in the exchange of data, materials,
and ideas.  In the case of a collaboration, inclusion of an agreement
of participants to adhere to group decisions on data ownership and
publication rights may be advantageous.

If several independent investigators have entered into a collaboration,
it is necessary to identify a specific investigator who will act as the
group coordinator.  All applications submitted as components of a
collaboration MUST cite the group coordinator on page 2 under "Key
Personnel Engaged on Project" of the form PHS 398.  Direct costs
related to this coordinating activity may not exceed $50,000 per year.
These funds would be in addition to the funds (up to $160,000) related
to the research activities proposed by the coordinating institution.



NIH and ADAMHA policy is that applicants for NIH/ADAMHA 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 in Section 2, 1-4
of the Research Plan and summarized in Section 2, E, 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,

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 will be 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 June 18, 1992.  The letter of intent is to include the names
of the Principal Investigator/program director and principal
collaborators, descriptive title of the potential application, and
identification of the organization(s) involved.  The letter of intent
is to be sent to the Chief, Review Branch, NIDDK, at the address noted
below under "Application Procedures."

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.


Applications are to be submitted on form PHS 398 (rev. 9/91) which 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 two of page one of the
application and enter the title "Genes Responsible for Diabetes" and
the RFA number DK-92-14.  As indicated under "Mechanism of Support," if
a collaboration of individual investigators is planned, it is necessary
to identify one of the investigators as the group coordinator and to
cite this individual in all applications on page 2 of the form PHS 398.

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.

Applications must be received by July 22, 1992.  If an application is
received after that date, it will be returned to the applicant.
Applicants who have entered into a collaboration may submit the
applications individually with a cover letter noting their involvement
and listing the other members of the collaboration.  The original,
including the Checklist, and three copies of the application must be
sent or delivered 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 NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, as determined by NIDDK staff,
the applicant will be contacted 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.

In the event that the number of applications is large compared to the
number of awards to be made, the NIH may conduct a preliminary
scientific peer review (triage) to eliminate those applications that
are clearly not competitive.  The NIH will administratively withdraw
from competition those applications judged to be noncompetitive and
notify the applicant and institutional business official.

Competitive applications will be assigned to a special peer review
group convened by the NIDDK.  Following review by the initial review
group, the applications will be considered by the National Diabetes and
Digestive and Kidney Diseases Advisory Council in February 1993.

Applications in response to this solicitation 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
women.  For those applications that propose collaborative efforts
between several applicants, additional factors to be considered during
the review would include the efficacy of the collaboration, the
commitment of the participants to the collaboration, the design and
responsibilities of the coordinating center and the cost effectiveness
of the collaborative effort.


The anticipated date of award is April 1, 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 Specialist
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


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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