RESEARCH ON SKELETAL GROWTH AND DEVELOPMENT

Release Date:  September 16, 1998

PA NUMBER:  PA-98-105

P.T.

National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute for Child Health and Human Development
National Institute of Dental Research
National Institute of Diabetes, Digestive, and Kidney Diseases

PURPOSE

The National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS), the National Institute for Child Health and Human Development (NICHD),
the National Institute of Dental Research (NIDR), and the National Institute of
Diabetes, Digestive, and Kidney Diseases (NIDDK) encourage investigator-initiated
research grant applications to study axial, appendicular, and craniofacial
skeletal growth and development.  The purpose of this Skeletal Growth and
Development Program Announcement (PA) is to inform the scientific community of
our interests, and to stimulate and foster a wide range of basic, translational
and patient-oriented clinical studies, in skeletal growth and development.
Applications are encouraged to study skeletal growth and development from the
perspectives of mechanisms of pattern formation, cartilage induction,
endochondral ossification, intramembranous bone formation, biomechanics, and the
clinical treatment of the resulting disorders.

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, Research on Skeletal Growth and
Development, 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 foreign and domestic, 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 from minority individuals, women, and persons
with disabilities are encouraged.

MECHANISM OF SUPPORT

The mechanism of support will be the research project grant (R01); applicants are
advised to contact the program officials listed under INQUIRIES for information. 
Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  Awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy statement
(April 1, 1994).

RESEARCH OBJECTIVES

Background

Disturbances in skeletal growth and development cause a wide variety of clinical
disorders.  These disorders can involve any part of the musculoskeletal system. 
They can be localized to a specific anatomic region, or can extend throughout the
musculoskeletal system.  They vary in severity from asymptomatic lesions to
lethal, generalized skeletal dysplasias.  Representative examples include, but
are not limited to, joint dysplasias, slipped capital femoral epiphysis,
scoliosis, clubfoot, spina bifida, and failure of normal bone growth manifested
as dwarfism.  The disturbances that lead to joint dysplasias and malformations
may lead to the early onset of degenerative osteoarthritis, which affects
approximately 500,000 people in the United States.  Adolescent idiopathic
scoliosis, one type of this condition, has a prevalence of 25 per 1,000 in the
population.  As a group, these disturbances have significant economic and human
impact, as relates to functional limitations and the potential for a reduced
quality of life.

Recently, there have been significant scientific advances defining the sequential
expression of genes responsible for the synthesis of matrix molecules and
formation and growth of the musculoskeletal system.  Additional observations have
identified the critical roles of certain cytokines in controlling cell
proliferation and matrix synthesis.  However, few of these discoveries have been
translated into treatment advances of the  multiple clinical conditions that
result from disturbances in molecular mechanisms.  Dramatic improvement in
treatment may require a new level of understanding, one that incorporates the
combined efforts of cell and molecular biologists, morphologists, clinicians, and
bioengineers.

The current PA indicates our continued interest in skeletal growth and
development, and is the direct outgrowth of a NIAMS, NICHD, American Academy of
Orthopaedic Surgeons, and Orthopaedic Research and Education Foundation-sponsored
workshop on the status and future research directions on Skeletal Growth and
Development, held in May 1997.  The specific aims of this multidisciplinary 
workshop were to: (1) define the current knowledge of skeletal morphogenesis and
growth, including the formation of the bony skeleton and the synovial joints, and
current knowledge of disturbances of skeletal morphogenesis and growth; (2)
identify potential applications of basic knowledge of skeletal growth,
development and morphogenesis to clinical problems; (3) identify future research
directions that will advance understanding of skeletal growth, development, and
morphogenesis, and the relationship of disturbances in these processes to the
development of clinical disorders; and (4) to identify future research directions
that will increase the ability to maintain and regenerate musculoskeletal
tissues.  To accomplish these aims, a multidisciplinary group of basic scientists
and clinicians were assembled to define our current knowledge and to identify
future cross-cutting, research directions.  A more detailed description of the
proceedings and suggested research topics can be found in Skeletal Growth and
Development:  Clinical Issues and Basic Science Advances, which can be obtained
from the  American Academy of Orthopaedic Surgeons, Chicago, Illinois.  Although
not the subject of the referenced meeting, it is in the interests of the NIH to
include in this Program Announcement related research in the areas of
craniofacial skeletal growth and development.

Scope of Research Sought

Through the use of this PA, the sponsoring Institutes anticipate the receipt of
a broad range of applications targeted, but not limited, to the following areas
related to axial, appendicular, and craniofacial skeletal growth and development:

o  Mechanisms of pattern formation, cartilage induction, endochondral
ossification, and intramembranous bone formation Control of angiogenesis in bone
morphogenesis and growth.
o  Mechanism(s) by which cells are responsive to electrical or other physical
stimuli.
o  Regulation and importance of programmed cell death in the maintenance and
pathology of skeletal tissues.
o  Nature and functional consequences of cell-cell and cell-matrix interactions
during skeletogenesis.
o  Cellular and molecular differences between intramembranous and endochondral
bone formation.
o  Effects of distraction and compression on growth plate function.
o  Identification and role of growth factors, transcription factors, etc. in the
initiation of cartilaginous rudiment formation.
o  Regulation of chondrocyte maturation in the growth plate.
o  Mechanisms of signal transduction in the growth plate.
o  Mechanisms of fracture healing.
o  Developmental processes influencing bone healing or remodeling. Role of the
joint interzone in endochondral bone development.
o  Identification of patterning defects resulting in skeletal abnormalities.
o  Development of improved animal models to study disturbances of axial,
appendicular, and craniofacial skeletal morphogenesis and growth.
o  Role of growth factors in the development of peak skeletal mass and the
healing of articular cartilage.
o  Role of skeletal factors in tooth eruption.

Biomechanical and clinical applications
o  Role of joint congruence and stability in the development of synovial joints.
o  Factors responsible for bar formation in the physis, and for its successful
excision.
o  Effects of growth on the scoliotic spine following posterior spinal fusion.
o  Pathophysiology of hip dysplasia and dislocation (e.g., joint congruence and
stability in developing synovial joints) and their surgical management, to
justify treatment  approaches.
o  Mechanisms of manipulative, bracing and surgical corrections of axial,
appendicular, and craniofacial skeletal deformities, the stability of effects
over time, and the effectiveness/outcomes of such treatments.

No priority has been established among the research suggestions presented. 
Applications are encouraged in any scientifically meritorious research area
related to skeletal growth and development.  Research applications are encouraged
from all basic science disciplines pertinent to this area, as well as the various
clinical specialties providing health care services for these patients.

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
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

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 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994 available on the web at the following URL address: 
http://www.nih.gov/grants/guide/notice-files/not98-024.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies 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 Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC-7910, Bethesda, MD 20892-7910 telephone: (301) 710-0267; Email: 
GrantsInfo@nih.gov. The title and number of the program announcement must be
typed in Section 2 on the face page of the application.

The completed original application and five legible copies must be sent or
delivered to:

CENTER FOR SCIENTIFIC REVIEW
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 on the basis of established PHS referral
guidelines.  Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer review group convened in accordance with
standard 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

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written review, comments on the following aspects of the application will be made
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in the assignment of the overall score.

(1) Significance.  Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

(2) Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

(3) Innovation.  Does the project employ novel concepts, approaches, or methods? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

(4) Investigator.  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

(5) Environment.  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

In addition to the above criteria, and in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

(1) The adequacy of plans to include both genders, 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.

(2) The reasonableness of the proposed budget and duration in relation to the
proposed research.

(3) The adequacy of the proposed protection for humans, animals, or the
environment, to the extent they may be adversely affected by the project proposed
in the application.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions: 
quality of the proposed project as determined by peer review; availability of
funds; and program relevance and balance among research areas of the program
announcement.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

James S. Panagis, M.D., M.P.H.
Orthopaedics Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-37K, MSC 4500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  panagisj@ep.niams.nih.gov

A. Tyl Hewitt, Ph.D.
Developmental Biology, Genetics and Teratology Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B01F, MSC-7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5541
FAX:  (301) 402-4083
Email:  th119v@nih.gov

Norman Braveman, Ph.D.
Inherited Diseases and Disorders
National Institute of Dental Research
45 Center Drive, Room 4AN-24D, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-2089
FAX:  (301) 480-8318
Email:  bravemann@de45.nidr.nih.gov

Ronald N. Margolis, Ph.D.
Senior Advisor for Molecular Endocrinology
National Institute of Diabetes, Digestive, and Kidney Diseases
45 Center Drive, Room 5AN-12J, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8819
FAX:  (301) 435-6047
Email:  rm76f@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Vicki Maurer
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-49A, MSC 4500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  maurerv@ep.niams.nih.gov or curlingn@ep.niams.nih.gov

Mr. E. Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1303
FAX:  (301) 402-0915
Email:  shawverd@exchange.nichd.nih.gov

Mr. Martin Rubinstein
Grants Management Branch
National Institute of Dental Research
45 Center Drive, Room 4AN-44A, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email:  mr49c@nih.gov

Ephraim Johnson
Grants Management Specialist
National Institute of Diabetes, Digestive, and Kidney Diseases
45 Center Drive, Room 6AN-44D, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8856
FAX:  (301) 480-3504
Email:  johnsone@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.846  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 grant policies and Federal regulations 42 CFR Part 52
and 45 CFR Part 74.  This program is not subject to 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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