Full Text PA-96-076
 
ANABOLIC HORMONES IN BONE: BASIC RESEARCH AND THERAPEUTIC POTENTIAL
 
NIH GUIDE, Volume 25, Number 33, October 4, 1996
 
PA NUMBER:  PA-96-076
 
P.T. 34

Keywords: 
  Hormones 
  0715031 

 
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Dental Research
National Institute on Aging
 
PURPOSE
 
The objective of this initiative is to elicit grant submissions which
focus on systemic hormones, local growth factors, and bone-active
cytokines which may have specific or generalized anabolic effects on
bone.  While the primary focus is on basic research, the long-term
emphasis is on identifying mechanisms or processes related to hormone
action with potential applicability as targets for therapeutic agents
for the treatment of diseases which adversely affect bone, including
osteoporosis and primary hyperparathyroidism.
 
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 PA,
Anabolic Hormones in Bone:  Basic Research and Therapeutic Potential,
is related to the priority area of 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
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.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) (R29) award.  Racial/ethnic
minority individuals, women, and persons with disabilities are
encouraged to apply as principal investigators.
 
MECHANISM OF SUPPORT
 
Support for this Program Announcement will be through the NIH
research project grant (R01) and FIRST (R29) award mechanisms.
Applicants will be responsible for the planning, direction, and
execution of the proposed project.  Applications submitted in
response to this PA will compete for funds with other regular
research project grant applications.
 
Applications 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.
 
The award of grants in response to this PA is also contingent upon
the availability of funds.  Awards will be administered under PHS
grants policy as stated in the PHS Grants Policy Statement (rev.
4/94).
 
RESEARCH OBJECTIVES
 
Background
 
Diseases that affect bone, such as osteoporosis and primary
hyperparathyroidism, result in gradual loss of bone.  This
osteopenia, or thinning of the bones, is a leading cause of fractures
in the adult, and is particularly prevalent in women. Hormones are
major regulators of bone mass and osteopenia may result from
alterations in hormone action, such as loss of normal estrogen
production in post-menopausal women, excessive production of
parathyroid hormone (PTH) as in primary hyperparathyroidism, or
glucocorticoid excess as a consequence of chronic steroid use in
immunosuppressive therapy. Other imbalances in local growth factors
and/or bone-active cytokines resulting from a variety of conditions
may also contribute to osteopenia.  Limited clinical trials have been
initiated to determine whether hormone replacement can mitigate or
reverse the osteopenia associated with menopause, hypogonadism or
primary hyperparathyroidism.  To date therapeutic agents have been
restricted to compounds which alter mineral content and/or molecular
structure of bone (e.g., bisphosphonates) or alter hormonal balances
(e.g., estrogen replacement therapy, calcitonin, vitamin D).
Unintended or undesired side effects limit effectiveness of such
agents.
 
This initiative stems from an NIDDK Workshop entitled: "Anabolic
Hormones in Bone: Basic Research and Therapeutic Potential" which was
held May 1-2, 1995 (see Margolis et al., Journal of Clinical
Endocrinology and Metabolism 81 (3):872-77, 1996), and co-sponsored
by NIAMS and the NIH Office of Research on Women's Health. The
workshop focused on hormones, growth factors, and cytokines which
express positive, anabolic effects on bone mass, either directly or
indirectly.  The workshop identified several key issues essential to
the development of agents with potential anabolic effects on bone,
including: efficacy, mechanism of action, specificity, ease of use,
and long-term benefit. This initiative is therefore designed to
elicit grant submissions which focus on systemic hormones, local
growth factors, and bone-active cytokines which may have specific or
generalized anabolic effects on bone.  While the primary focus is on
basic research, the long-term emphasis should be on identifying
mechanisms or processes associated with hormonal regulation of bone
cell structure/function with potential applicability as therapeutic
agents for the treatment of diseases which adversely affect bone,
including osteoporosis and primary hyperparathyroidism.
 
Research Objectives and Scope
 
The major areas of interest and potential that have been identified
relevant to this program announcement are the following:
 
o  The mechanism(s) of action of sex steroids, including estrogen,
estrogen agonists, partial agonists, and agents with estrogen-like
activity in bone; androgens and androgen-like agents which express
positive, anabolic effects on bone.
 
o  Other members of the steroid/thyroid/retinoid superfamily,
including vitamin D which may have positive effects on net bone mass.
 
o  Parathyroid hormone (PTH) and/or parathyroid hormone-related
peptide (PTHrP) and agonists or partial agonists which express PTH-
or PTHrP-like anabolic effects in bone.
 
o  Insulin-like growth factor I (IGF-I), IGF-I binding proteins, or
any other component of the IGF axis which might help to safely
express the positive effects of IGFs on bone.
 
o  Fibroblast growth factor(s) and their role(s) in bone/cartilage
development and/or angiogenesis related to bone.
 
o  Members of the Bone Morphogenetic Protein family (e.g., TGFs).
 
o  Colony-stimulating factor-1.
 
o  Prostaglandins with effects on bone cells.
 
o  Interleukins, including those that have positive effects and
agents which can oppose putative negative effects on bone.
 
This is by no means a complete listing of potentially important
agents.  The general focus should be on developing an understanding
of the putative mechanism(s) of action of these agents with the goal
of defining what aspect(s) of bone metabolism is/are affected and how
anabolic actions may be achieved and sustained.  The mission of the
NIDDK is to provide broad fundamental and clinical research support
for a spectrum of chronic and disabling diseases which affect bone,
including osteoporosis and primary hyperparathyroidism. Applications
for research focusing primarily or solely on craniofacial bone will
be assigned to the National Institute of Dental Research.
Applications that address changes in the levels of, and biologic
responses to, these bone regulatory factors as a consequence of aging
may be relevant to the National Institute on Aging.
 
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 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 20, 1994 (FR 59 14508-14513) 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.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Office 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@odrockm1.od.nih.gov.
 
The program announcement title and number must be typed on line 2 of
the face page of the application form and the YES box must be marked.
 
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 completed original application and five legible copies must be
sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned to initial review groups for review and
to Institutes/Centers for possible funding on the basis of
established Public Health Service referral guidelines.  Applications
that are complete 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, generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council or board.
 
Review Criteria
 
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 the resources necessary to perform the research;
 
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, 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 which are not readily
available in the United States or which provide augmentation of
existing U.S. resources.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other approved
applications.  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 priority.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Ronald N. Margolis, Ph.D.
Endocrinology Section
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 5AN-12J
Bethesda, MD  20892-6600
Telephone:  (301) 594-8819
FAX:  (301) 480-3503
Email:  rm76f@nih.gov
 
William Sharrock, Ph.D.
Bone Biology Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-43E, MSC 4500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  william_sharrock@nih.gov
 
Linda A. Thomas, Ph.D.
Craniofacial Development and Disorders Program
National Institute of Dental Research
45 Center Drive, Room 4AN24J
Bethesda, MD  10892-6402
Telephone:  (301) 594-2425
FAX:  (301) 480-8138
Email:  THOMASL@DE45.NIDR.NIH.GOV
 
Sherry Sherman, Ph.D.
Geriatrics Program
National Institute on Aging
Gateway Building, Suite 3E327
Bethesda, MD  20892-9205
Telephone:  (301) 435-3048
FAX:  (301) 402-1784
Email:  shermans@gw.nia.nih.gov
 
Direct inquiries regarding fiscal and administrative matters to:
 
Kim Law
Grants Management Specialist
Building 45, Room 6AS-49A
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive
Bethesda, MD  20892-6600
Telephone:  (301) 594-8869
 
Vicki Maurer
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-49A, MSC 4500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3504
FAX:  (301) 480-4543
Email:  vicki_maurer@nih.gov
 
Mr. Martin R. Rubinstein
National Institute of Dental Research
45 Center Drive, Room 4AN44A
Bethesda, MD  20892-6402
Telephone  (301) 594-4800
FAX:  (301) 480-8301
E-mail:  Martin.Rubinstein@NIH.GOV
 
Robert Pike
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  28092-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  pikeb@gw.nia.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.847 (NIDDK), 93.846 (NIAMS), 93.121 (NIDR), and
93.866 (NIA).  Awards are 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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