BASIC RESEARCH ON BIOMECHANICAL SIGNALING MECHANISMS IN CARTILAGE

NIH GUIDE, Volume 26, Number 40, December 19, 1997

RFA:  AR-98-005

P.T.

National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute on Aging

Letter of Intent Receipt Date:  March 15, 1998
Application Receipt Date:  April 28, 1998

PURPOSE

The National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS) and the National Institute on Aging (NIA) invite applications for
basic research on mechanisms of biomechanical signaling in cartilage.  The
applications may be for individual research projects or for a group of
independent research projects that use the interactive research project grant
(IRPG) mechanism.  The research should be specifically targeted towards
understanding the signal transduction and regulatory pathways through which
articular cartilage chondrocytes sense and respond to mechanical stimuli. 
This Request for Applications (RFA) requests basic and applied research
projects, but not epidemiological or clinical treatment projects.

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 RFA, Basic Research on
Biomechanical Signaling Mechanisms in Cartilage, is related to the priority
areas of chronic disabling conditions and of older adults and preventive
services.  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. Racial/ethnic minority individuals, women,
and persons with disabilities are encouraged to apply as Principal
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual research
grant (R01) and interactive research project grants (IRPG) mechanisms.  The
IRPG mechanism encourages interaction and collaboration among independent
scientists with common goals.  It is intended to bring together research
projects from investigators who wish to collaborate but who do not require
extensive shared resources.  There should be constructive interchange of
ideas, data and/or materials.  A minimum of two independent investigators are
encouraged to submit concurrent, collaborative, cross-referenced individual
regular research project grant (R01) applications.  These applications must be
free-standing and contain independent hypotheses and aims.  An application
that provides only a service to other applicants is not acceptable. 
Applicants may be from one or several institutions.  Potential applicants
contemplating the submission of an IRPG should contact the program official
listed under  INQUIRIES  at an early opportunity.  Guidelines for preparing
IRPG applications are available from the program official or from the internet
at: http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html.

Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant.  The anticipated award date is
September 30, 1998.  Because the nature and scope of the research proposed in
response to this RFA may vary, it is anticipated that the size of an award
will also vary.  This RFA is a one time solicitation.  Future unsolicited
competing continuation applications will compete with all investigator
initiated applications and be reviewed according to customary peer review
procedures.

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 within the application.

FUNDS AVAILABLE

It is anticipated that six to eight awards will be made as a result of
applications for "Basic Research on Biomechanical Signaling Mechanisms in
Cartilage."  The estimated funds available for the first year of support for
the program are $1,250,000 dollars.  Actual funding is contingent upon receipt
of a sufficient number of scientifically meritorious applications.  Funding
beyond the first and subsequent years of the grant will be contingent upon
satisfactory progress during the preceding years and the availability of
funds.

RESEARCH OBJECTIVES

The purpose of this RFA is to stimulate basic research in mechanisms of
biomechanical signaling in cartilage.  Mechanical loading of articular
cartilage is required for normal growth and maintenance of the tissue, and
anomalous mechanical loading of the tissue can lead to joint damage.  Clinical
and experimental evidence indicates that removal of mechanical stimulation by
immobilization of a joint leads to suppression of matrix synthesis,
degradation of matrix components, and decreased growth.  Destabilization of
the knee, leading to abnormal loading conditions, may result in the
development of osteoarthritis.  The molecular mechanisms underlying these and
other mechanical effects are not well understood.

Recent progress in cell biology has delineated the importance of signaling
factors in controlling cellular functions and promoting cell survival for a
variety of cell types, but less is known about signaling pathways in
chondrocytes.  The roles of various different stimuli such as hydrostatic
pressure, membrane stretching, and fluid shear in the transduction of
mechanical forces into cellular activities remain unresolved.  Chondrocytes,
like other cells, exist in an information-rich environment containing
extracellular matrix macromolecules, cytokines, hormones, and remodeling
enzymes.  Transmembrane receptors detect and relay extracellular signals to
intracellular responsive elements and subsequently influence gene expression. 
Identification of cellular and molecular signaling mechanisms in cartilage and
their roles in normal and abnormal joints may not only provide key information
on the pathogenesis of osteoarthritis, but also may open  new sites for
potential therapeutic intervention. Appropriate research areas may include,
but are not limited to, the following:

o  Development of in vivo or in vitro systems that will allow analysis of
cellular responses to biomechanical stimuli;

o  Elucidation of biomechanical signal transduction pathways in chondrocytes;

o  Studies on mechanical regulation of  the structure/function of the
cartilage matrix;

o  Studies on the role of mechanical influences on the degradation and repair
of cartilage at the cellular level;

o  Analysis of biomechanical effects on chondrocyte metabolic activities,
responses to cytokines, gene expression and changes in osteoarthritis;

o  Age-related changes in cellular response to biomechanical stimuli,
including changes in turnover of cartilage, the signal transduction pathway,
and gene expression; and, effects of age-related changes in joint anatomy or
cartilage composition on biomechanical signaling.

This list is intended to be illustrative and not exclusive or restrictive.
Applications combining interdisciplinary approaches that include
collaborations between biomechanical engineers and cell biologists are
strongly encouraged.  Integration of mechanisms across a range of events such
as joint loading to molecular events at the cell membrane and gene expression
levels are also highly recommended.

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 so that research
findings can be of benefit to all persons at risk of the disease, disorder or
condition under study.  If women or minorities are excluded or inadequately
represented a clear compelling rationale must be provided.  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, Volume 23, Number
11, March 18, 1994.  This information is available on the internet at
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

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.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 15, 1998, 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 NIAMS 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:

Tommy L. Broadwater, Ph.D.
Scientific Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-25U, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-4952
FAX:  (301) 480-4543
Email:  broadwater@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in
applying for these grants.  These forms are available at most institutional
offices of sponsored research and from the Division 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@od.nih.gov
.

The RFA label available in the PHS 398 (rev. 5/95) 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 2 of the face page of the application
form and the YES box must be marked.

Submit a signed original of the application, including the Checklist, and
three signed copies in one package to:

CENTER FOR SCIENTIFIC REVIEW (formerly 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)

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

Tommy L. Broadwater, Ph.D.
Scientific Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-25U, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-4952
FAX:  (301) 480-4543
Email:  broadwater@nih.gov

Applications must be received by April 28, 1998.  If an application is
received after that date, it will be returned to the applicant without review. 
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and
responsiveness by the NIAMS and NIA staff.  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 that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened in
accordance with the 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
National Arthritis and Musculoskeletal and Skin Diseases Advisory Council and
the National Advisory Council on Aging.

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 method?
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?

In addition, the adequacy of plans to include both genders and minorities and
their subgroups as appropriate for the scientific goals of the research will
be reviewed.  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, and
conformance with the NIH Guidelines for the Inclusion of Women and Minorities
as Subjects in Clinical Research.

AWARD CRITERIA

The anticipated date of award is September 30, 1998.  Awards will be based
upon the following criteria:

o  scientific merit
o  availability of funds
o  programmatic priorities of the funding ICD
o  responsiveness to the RFA

INQUIRIES

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:

Bernadette Tyree, Ph.D.
Cartilage and Connective Tissue Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-37J, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5032
FAX:  (301) 480-4543
Email:  tyreeb@ep.niams.nih.gov

Chhanda Dutta, Ph.D.
Geriatrics Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3E-327, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 435-3048
FAX:  (301) 402-1784
Email:  duttac@exmur.nia.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Nancy Curling
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-43B, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3503
FAX:  (301) 480-4543
Email:  nc23a@nih.gov

Mr. Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  ellisj@gw.nia.nih.gov

Schedule

Letter of Intent Receipt Date:  March 15, 1998
Application Receipt Date:  April 28, 1998
Initial Review:  June, 1998
Second Level Review:  September 1998
Anticipated Award Date:  September 30, 1998

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.846.  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.

The PHS strongly encourages all grant 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
America people.


Return to Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.