Full Text DK-92-20


NIH GUIDE, Volume 21, Number 22, June 12, 1992

RFA:  DK-92-20

P.T. 34

  Musculoskeletal System 

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Letter of Intent Receipt Date:  July 10, 1992
Application receipt Date:  August 25, 1992


The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and the National Institute of Arthritis and Musculoskeletal and
Skin Diseases (NIAMS) invite investigator-initiated research grant
applications to elucidate the role(s) of systemic and local hormones,
growth factors, and cytokines on bone in health and disease.


The 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.  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 may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal Government.  Minority
individuals and women are encouraged to submit as Principal


Support of this program will be through the NIH research project grant
(R01) award. Responsibility for the planning, direction, and execution
of the proposed project will be solely that of the applicant.  Except
as otherwise stated in this announcement, awards will be administered
under PHS grants policy as stated in the PHS Grants Policy Statement.

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 applications
submitted in response to this RFA may not exceed five years.  A maximum
of three years may be requested for foreign awards.


For FY 1993, $2,000,000 will be committed by the NIDDK to fund
applications submitted in response to this RFA and an additional
$2,000,000 will be committed by the NIAMS.  However, this funding level
is dependent upon the receipt of a sufficient number of applications of
high scientific merit.  In order to help meet NIH goals for managing
the costs of biomedical research, applicants must limit requests to not
more than $160,000 direct costs for the initial budget period.
Although this program is provided for in the financial plans of the
NIDDK and the NIAMS, the award of grants pursuant to this RFA is also
contingent upon the availability of funds for this purpose.



Bone disease, particularly osteoporosis, is a major health problem,
prevalent primarily in women, that adversely affects large segments of
the population.  Approximately 1.5 million fractures occur each year in
the United States that may be attributable to osteoporosis, with major
and significant socioeconomic impact.  It is estimated that there is a
lifetime risk of hip fracture of 15-30 percent for women and 5-10
percent for men.  In 1986, the annual cost of osteoporosis was
estimated in the range of $7 to 10 billion.  Therefore, osteoporosis
accounts for a large component of health-care costs and human suffering
with attendant individual pain and loss of productivity.  Other bone
disorders, such as Paget's disease, renal osteodystrophy, and
hyperparathyroidism, also cause significant morbidity. Many of the
causes and potential treatments for bone disease have a basis in the
endocrinology of bone cell physiology.

Alterations in hormone production and/or action are major contributing
factors to osteoporosis and other disorders of bone.  Although many
clinical studies and trials have focused on understanding the
pathophysiology and potential pharmacologic therapeutics involved in
osteoporosis and other bone disorders, knowledge of basic concepts of
the hormonal regulation of bone cell development, structure, and
function is inadequate. Specifically, questions pertaining to the roles
of systemic hormones versus locally active growth factors and/or
cytokines on the cells that regulate bone mass need to be answered.  At
the molecular level, many of the effects of hormonal actions are
reflected in specific changes in gene expression.  The nature and
mechanisms of these changes in response to steroid and/or peptide
hormones requires definition.  The purpose of this solicitation is to
stimulate investigation of the role of systemic and local hormones and
other endocrine factors in bone physiology and pathobiology.  The
results of this research should enhance understanding of the hormonal
regulation of bone, contribute to the knowledge of the pathogenesis of
osteoporosis and other bone disorders, and ultimately lead to new
strategies for prevention and treatment of these disorders.


Some examples of research topics that would be considered responsive to
this solicitation include the following:

o  basic studies on the molecular and cellular action of estrogen,
other sex steroids, antiestrogens, 1,25(OH)2 D3, glucocorticoids,
retinoic acid, T3 and other members of the steroid/thyroid hormone
superfamily, and the analogues, on bone;

o  the effects of interactions between systemic hormones (e.g.,
PTH/PTHrP, calcitonin (CT), estrogen, thyroid hormone, Growth Hormone)
and local factors (e.g., IGF-I, cytokines) on bone;

o  the roles of local growth factors and/or cytokines and lymphokines
on the endocrine/paracrine/autocrine regulation in effecting hormonal
action on bone in health and disease;

o  studies of the mechanism of action by which CT and PTH/PTHrP act
through the novel G-protein subfamily of receptors in effecting
physiological regulation at the level of bone and other cells;

o  identification of the target genes for bone-active hormones/growth
factors/cytokines and elucidation of the regulatory elements involved;

o  mechanisms of hormonal signal transduction in bone cells,
identification of the type(s) of response that take place, and whether
or not different pathways mediate the responses to hormones with the
same end result

These areas of interest are not listed in any order or priority.  They
are only suggested examples of areas of research.  Applicants are
encouraged to propose other areas that are related to the objectives
and scope described above.


Interdisciplinary approaches may be needed for these studies with
expertise required in one or more of the following areas:  molecular
and cellular biology, endocrinology, physiology, pathology, and


NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be 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 should be addressed in developing a research
design and sample size appropriate for the scientific objectives of the
study. This information should be included in the form PHS 398 in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.  Applicants/offerors 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 Unites 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 includes 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.


Prospective applicants are asked to submit, by July 10, 1992, 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 is being 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 possible 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
Westwood Building, Room 605
5333 Westbard Avenue
Bethesda, MD  20892
Telephone:  (301) 496-7083


The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  The form is available from most
institutional business offices and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/496-7441.

The RFA label available in the PHS 398 application form must be affixed
to the bottom of the face page.  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 2a of the face page of the application
form and check the YES box.

Submit a signed, typewritten original of the application, including the
Checklist, and four signed, exact photocopies, in one package to:

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

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

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

Applications must be received by August 25, 1992.  If an application is
received after that date, it will be returned to the applicant.  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.  However, it is allowable to submit the same
project as both an R01 and as a component project of a program project.
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 previously reviewed.  Such
applications must not only include an introduction addressing the
previous critique but also be responsive to this RFA.


Upon receipt, applications will be reviewed by the Division of Research
Grants (DRG) for completeness. Incomplete applications will be returned
to the applicant without further consideration.  Evaluation for
responsiveness to the program requirements and criteria stated in the
RFA is an NIDDK staff function.  If the application is not responsive
to the RFA, NIDDK staff will contact the applicant to determine whether
it should be returned to the applicant or held until the next receipt
date and reviewed in competition with all other unsolicited

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.
Applications may be subjected to triage by an NIDDK peer review group
to determine scientific merit relative to other applications received
in response to this RFA.  If the number of applications submitted is
large compared to the number of awards to be made, a preliminary
scientific peer review may be conducted and applications withdrawn from
further competition if not competitive for the award.  The NIDDK will
notify the applicant and institutional official of this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the usual NIH peer
review procedures by an initial review group specifically convened for
this RFA. Following this review, the applications will be given a
secondary review by the NIDDK and NIAMS Advisory Councils unless not
recommended for further consideration by the initial review group.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific/technical merit criteria specific to the objectives of
the RFA;

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly, but not exclusively, in the area of the
proposed research;

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  if an application involves activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed means for protecting against or minimizing such effects.

The following additional criterion applies to applications from foreign

o  uniqueness of research such that it can only be performed outside of
the United States.


Letter of Intent Receipt Date:       July 10, 1992
Application Receipt Date:            August 25, 1992
Initial Review:                      October/November 1992
Second Level Review:                 January/February 1993
Anticipated Award:                   April 1, 1993


Applications will compete for available funds with all other
applications responsive to this RFA.  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 balance among the research areas represented in this RFA.

The anticipated date of award is April 1, 1993.


Written and telephone inquiries concerning this RFA are encouraged.

Direct inquiries regarding programmatic issues should be directed to:

Ronald N. Margolis, Ph.D.
Director, Endocrinology Research Program
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 621
Bethesda, MD  20892
Telephone:  (301) 496-7504

Joan A. McGowan, Ph.D.
Chief, Bone Biology and Bone Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 403
Bethesda, MD  20892
Telephone:  (301) 480-7881

Direct inquiries regarding fiscal matters should be directed to:

Sharon Tempchin
Grants Management Specialist, DEA
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 496-7467

Carol Clearfield
Grants Management Specialist
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 403
Bethesda, MD  20892
Telephone:  (301) 496-7495


This program is described in the Catalog of Federal Domestic Assistance
sections 93.847 and 93.846.  Awards will be made under the authority of
the Public Health Service Act, Title III, Section 301 (Public Law
78-410, as amended; 42 USC 241) and administered under PHS grant
policies and Federal Regulation 42 CFR Part 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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