Full Text AR-94-005


NIH GUIDE, Volume 23, Number 13, April 1, 1994

RFA:  AR-94-005



National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Aging

Letter of Intent Receipt Date:  June 28, 1994
Application Receipt Date:  July 26, 1994


The Bone Biology and Bone Diseases Branch of the National Institute
of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the Bone
and Mineral Research Program of the Endocrinology Research Section of
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), and the Geriatrics and Biology of Aging Programs of the
National Institute on Aging (NIA) invite investigator-initiated
research project grant applications to encourage and facilitate
research projects designed to develop promising basic cellular,
molecular, physiological, and genetic approaches to osteoporosis.


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), Basic Osteoporosis New Experimental
Strategies, is related to the priority areas of diabetes and chronic
disabling conditions and older adults and preventive services.
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.
Applications may be submitted by single institutions and by a
consortia of institutions.  Foreign institutions are not eligible for
First Independent Research and Support and Transition (FIRST) (R29)
awards.  Applications from minority individuals and women are


Support for this program will be through investigator-initiated
research grant applications (R01) and FIRST (R29) awards.

This RFA is a one-time solicitation for fiscal year 1995.  However,
the NIAMS, NIDDK, and NIA may reissue the RFA in future years.  If
there is a continuing program need, the NIAMS, NIDDK, and NIA will
invite recipients of awards under this RFA to submit competitive
continuation applications.

Responsibility for planning and implementation of the proposed
project will be solely that of the applicant.  The total project
period for R01 applications submitted in response to the present RFA
may not exceed four years.  FIRST awards must be for five years.  The
anticipated award date is April 1, 1995.


Approximately $2,000,000 in total costs per year for four years will
be committed by the NIAMS to fund applications submitted in response
to this RFA. An additional $500,000 will be committed by the NIDDK,
and an additional $600,000 by the NIA.  This funding level is
dependent on the receipt of a sufficient number of applications of
high scientific merit.  The direct cost of each R01 project is
limited to $160,000 for the first year and R29s are limited to
$70,000.  Thus it is anticipated that a total of 12 to 14 projects
will be funded in FY 95.  Although this program is provided for in
the financial plans of the NIAMS, NIDDK, and NIA, the award of
grants, as well as the final amounts awarded, will be contingent upon
the availability of funds for this purpose.

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.



Much work remains to be done in order to counter the disabling,
costly consequences of osteoporosis.  Means of targeting nutritional
and pharmacological preventive strategies to individuals most at risk
for bone loss are needed in order to reduce the incidence of
fractures and the attendant costs to society.  Alternatives to the
available preventive drug therapies are needed in order to extend
their utility to the largest possible number of people.  Effective
approaches to the treatment of established osteoporosis are urgently
needed.  Such new therapeutic approaches are most likely to arise
from improved understanding of the basic biology of bone growth and

Recent scientific and technological developments have markedly
expanded opportunities for understanding the molecular and genetic
basis of osteoporosis.  Details are beginning to emerge of the
complex network of signalling mechanisms that control bone growth and
maintain skeletal integrity.  Specific probes have made it possible
to identify new molecules responsible for the local and systemic
regulation of bone cell function, as well as the cell surface
molecules and linked signal transduction pathways that mediate their
effects.  In particular, the complex relationship between the bone
microenvironment and the immune system demands attention.  The
identification, mapping, and structural analysis of genes with
crucial functions in the regulation of bone are increasingly feasible
research goals.  The use of genetically manipulated animals allows
investigators to test the effects of specific gene inactivation or
over-expression.  The identification of genetic variations in the
human population that underlie different vulnerabilities to bone loss
is made possible by the increasing knowledge of the human genome and
advancing molecular screening technology.

In order to capitalize on these opportunities, it is necessary to
integrate biological insights and methodologies from a broad range of
specialties.  The overall goal of the Basic Osteoporosis New
Experimental Strategies (BONES) initiative is to encourage and
support new basic research in the areas of bone structure, formation,
remodeling, and repair.  This initiative is designed to (1) encourage
established bone biology investigators to address
osteoporosis-related problems with novel approaches and the most
powerful methodologies available; (2) increase the pool of
investigators working in osteoporosis-related basic science areas by
drawing researchers from genetics, cell and molecular biology, and
structural chemistry into bone research; and (3) foster the
development of interactions between laboratories originating in
different disciplines.

Research Goals and Scope

Some examples of research areas in which applications would be
considered responsive to this RFA include, but are not limited to:

o  Mechanisms of action of growth factors, cytokines, bone inductive
factors, and other regulators of bone growth and remodeling;

o  Genes and gene products with critical roles in bone growth and

o  Mechanisms of action of estrogens, androgens, and glucocorticoids
on bone;

o  Origins and lineages of osteoblasts, osteoclasts, and osteocytes:
nature of precursor cells; control of activation, proliferation, and
differentiation; role of marrow stromal stem cells;

o  Mechanisms of regulation of bone growth and remodeling by physical
forces: loading stress, exercise, immobilization, and microgravity;

o  Biochemical and genetic markers of osteoporosis;

o  Biomechanical and non-invasive assessment of bone quality and

o  Influence of extracellular matrix composition and architecture on
bone; growth and remodeling in normal and pathologic conditions;

o  Relationship between bone formation and vascularization in normal
bone growth and fracture repair;

o  Cell and animal models for osteoporosis;

o  Effects of age and age-related changes on the level and action of
hormones, growth factors, cytokines, and other osteotropic/osteogenic
factors, and the impact and underlying mechanisms of such changes on
bone remodeling and repair;

o  Elucidation of the nature and underlying mechanisms of age-related
changes in the activation, proliferation and differentiation of bone
cells and bone cell precursors; and

o  Determination of the mechanisms and consequences of age-related
changes in bone vascularization and extracellular matrix on bone
remodeling and bone architecture.

Investigators are not limited to the above examples of research
areas, and are encouraged to propose other approaches that are
appropriate to the R01 and R29 mechanisms and the requirements of
this RFA.



It is the policy of the NIH that women and members of minority groups
and their subpopulations 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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

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 9, 1994 (FR 59 11146-11151) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

(NOTE:  When the proposed study or studies in the RFA or PA involves
a gender specific study or a single or limited number of minority
population groups, this should also be stated to inform potential
applicants and reviewers.)


Prospective applicants are asked to submit, by June 28, 1994, 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 subsequent applications, the information
that it contains allows NIH 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 Dr. William Sharrock at the
address listed under INQUIRIES.


The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for this RFA.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301-710-0267; and from the NIH program staff listed under

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

The RFA label available in the PHS 398 (rev. 9/91) 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 2a 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, and three signed photocopies, 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 also be sent to:

Dr. Tommy Broadwater
Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 406
Bethesda, MD  20892
Telephone:  (301) 594-9979
FAX:  (301) 594-9673

Applications must be received by July 26, 1994.  If an application is
received after that date, it will be returned to the applicant
without review.  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 for completeness by the
DRG and responsiveness by the NIAMS.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NIAMS 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 NIAMS 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 NIAMS.  The second
level of review will be provided by the NIAMS, NIDDK, and NIA
advisory councils.

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

o  extent to which the proposed research addresses the goals of the

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  adequacy of plans for overall collaboration;

o  availability of the resources necessary to perform the research;

o  adequacy of the mechanisms for quality control, study monitoring,
data management and reporting and data analysis;

o  adequacy of provisions for the protection of human subjects;

o  adequacy of the plans for inclusion of females and minorities; and

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


The anticipated date of award is April 1, 1995.  In addition to the
technical merit of the application as reflected in the priority
score, the NIAMS, NIDDK, and NIA will consider how well the applicant
institution meets the goals and objectives of the program as
described in the RFA, availability of resources and/or study


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:

William Sharrock, Ph.D.
Bone Biology and Bone Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 403
Bethesda, MD  20892
Telephone:  (301) 594-9975
FAX:  (301) 594-9673

Ronald Margolis, Ph.D.
Endocrinology Research Section
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 621
Bethesda, MD  20892
Telephone:  (301) 594-7549
FAX:  (301) 594-9011

Sherry Sherman, Ph.D.
Geriatrics Program
National Institute on Aging
Gateway Building, Suite 2C218
7201 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-932
FAX:  (301) 402-2945

Direct inquiries regarding fiscal matters to:

G. Carol Fitzpatrick
Grants Management Office
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 722A
Bethesda, MD  20892
Telephone:  (301) 594-9974
FAX:  (301) 594-9950


This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.846, 93.847, and 93.866.  Awards will be made
under the authority of the Public Health Service Act, Title III,
Section 301 (Public Law 410, 78th Congress, as amended, 42 USC 241
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 Public Health Service (PHS)
strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products.  This is
consistent with the PHS mission to protect and advance the physical
and mental health of the american people.


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