Full Text DE-95-002

ETIOLOGY AND PATHOGENESIS OF TEMPOROMANDIBULAR DISORDERS

NIH GUIDE, Volume 24, Number 15, April 28, 1995

RFA:  DE-95-002

P.T. 34

Keywords: 
  Oral Diseases 
  Pathogenesis 
  Etiology 
  Musculoskeletal System 


National Institute of Dental Research
Office of Research on Women's Health

Letter of Intent Receipt Date:  September 1, 1995
Application Receipt Date:  October 24, 1995

PURPOSE

The National Institute of Dental Research (NIDR) and the Office of
Research on Women's Health (ORWH) invite applications to support
research clarifying the etiology and pathogenesis of disorders
producing persisting pain or dysfunction within the temporomandibular
joint or masticatory muscles (temporomandibular disorders or TMDs).
Research also may include the development of appropriate models to
study normal function and pathological changes in the masticatory
muscles and temporomandibular joint (TMJ) and to clarify
biobehavioral processes influencing muscle or joint function or
pathology.  Studies that elucidate mechanisms underlying the higher
prevalence of these disorders in women are also encouraged.

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,
Etiology and Pathogenesis of Temporomandibular Disorders, is related
to the priority area of oral health and the cross-cutting issue of
women's health.  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, Governing Printing Office, Washington, DC 20402-9325
(telephone 202-783-3238).

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 to apply for First Independent
Research Support and Transition (FIRST) (R29) awards.  Applications
from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

The mechanisms of support utilized will be the individual research
project grant (R01) and the FIRST (R29) award.  Responsibility for
the planning, direction, and execution of the proposed project will
be solely that of the applicant.  The total project period for an
application submitted in response to this RFA may not exceed five
years.  It is anticipated that most R01 applicants will request no
more than three years of support.  This RFA is a one-time
solicitation for applications for new and competing renewal awards.
Future competitive renewal applications will compete with all
investigator-initiated applications and will be reviewed according to
customary referral and review procedures.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for
the first year of support for all awards under this RFA will be
$1,770,000.  The NIDR and the ORWH plan to fund a total of
approximately seven to nine grants in FY 1996.  This level of support
assumes receipt of a sufficient number of applications of high
scientific merit.  Applications may not request more than four
percent annual increases for inflation over subsequent years.
Although this program is provided for in the financial plans of the
NIDR and the ORWH, awards pursuant to this RFA are contingent upon
the availability of funds for this purpose.  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

Background

The principal signs and symptoms of the TMDs are pain in the jaw
region, including pain and tenderness in the masticatory muscles
and/or the temporomandibular joints, sometimes combined with
limitations or disturbance of mandibular movements (e.g., jaw
"locking," restricted jaw opening, or chewing problems).  Such signs
and symptoms often occur in the context of etiologically distinct
disorders, adding complexity to differential diagnosis.

Some of the TMDs appear to arise directly from degenerative or
inflammatory changes within the TMJ.  Others appear to reflect
increased vulnerability to injury or disruptions of reparative
processes following macro- or micro-trauma within the TMJ or
masticatory muscles.  Abnormalities in muscle function or structure
also may contribute to the persistent muscle fatigue and soreness
commonly reported.  Behavioral factors also appear to contribute to
the onset or exacerbation of symptoms for some patients with TMDs.
However, the dearth of rigorous basic science studies which focus on
the biological bases for the TMDs prompts the emphasis seen in this
RFA on biological aspects of etiology and pathogenesis.

The signs or symptoms associated with the TMDs are relatively common.
A recent meta-analysis indicated that an average of 30 percent of
subjects studied in 23 predominantly European prevalence studies
reported such signs or symptoms.  Using narrower criteria for TMD-
related pain, investigators evaluating a large sample of adults
enrolled in a U.S. health maintenance organization (HMO) concluded
that persisting or recurrent jaw pain affects more than 10 percent of
adults at any one time and one in three adults at some time over
their life span.  Studies also suggest that the TMDs can lead to
significant disruptions in functional activities such as chewing or
speaking, can impair social and personal functioning, and diminish
overall quality of life.  Aggressive treatment approaches to the
TMDs, including surgical reconstruction particularly with the use of
alloplastic implants, have resulted in severe disability.

A preponderance of females have been noted in most studies of
patients seeking care for the TMDs.  Initially, this was thought to
reflect gender-related differences in health care seeking behaviors
or differences in tolerance for pain and other physical symptoms.
However, several recent epidemiological studies indicate overall
associations between female gender and vulnerability to joint and
muscle disorders.  Such findings suggest the need to evaluate how
hormonal or other gender-related factors influence the development of
disorders, such as the TMDs, involving joints and muscles.

Although there is not universal agreement on a classification schema
for the TMDs, many U.S. clinical scientists have begun using a set of
research diagnostic criteria that categorizes clinical TMD conditions
within three broad clusters (i.e., muscle diagnoses; disc
displacements; and joint disorders consisting of arthralgia,
osteoarthritis of the TMJ, and osteoarthrosis of the TMJ) and
additionally categorizes each patient according to levels of pain-
related disability and psychosocial characteristics.

Two NIH-sponsored meetings held during 1994 summarized available
scientific information on the TMDs and identified promising research
directions.  Both the International Workshop on the TMDs and Related
Pain Conditions and the Workshop on TMJ Alloplastic Implants and
Local/Systemic Response, were sponsored by the NIDR, with co-
sponsorship from the National Institute of Arthritis and
Musculoskeletal Disorders (NIAMS), the NIH's Office of Research on
Women's Health (ORWH), the Agency for Health Care Policy and Research
(AHCPR), and the Food and Drug Administration (FDA).  At both
meetings participants recommended a major expansion of research to
clarify the etiology and pathogenesis of these conditions.  Topics
included in this RFA reflect key recommendations relevant to
etiology/pathogenesis emerging from these workshops.

Scope of Research Sought

Basic science and clinical research studies are sought that will
contribute to the understanding of biological processes underlying
various TMDs.  Studies of both normal and pathological conditions in
the masticatory muscles and the TMJ fall within the scope of this
RFA, as do studies of biobehavioral processes directly influencing
muscle or joint function or pathology.  Examples of some pertinent
areas and research topics are listed below.  This list is intended to
be illustrative, not exhaustive.  Topics are not presented in any
particular priority order:

o  Determine the molecular and cellular composition of normal and
abnormal tissues of the TMJ, masticatory muscles and ligaments,
identifying molecular mechanisms involved in the synthesis,
maintenance, and degradation of these tissues.

o  Characterize neural plasticity at the molecular, cellular, and
physiological level in response to injuries involving the TMJ and
masticatory muscles (including the introduction of artificial
materials or devices).

o  Define central nociceptive pathways activated in response to
injury of the TMJ, masticatory muscles, or other orofacial tissues
and characterize modulatory processes influencing such activation.

o  In relationship to alloplastic implant materials used in TMJ
repair, identify how cellular, humoral, genetic, and
neuroendocrine/hormonal factors are associated with individual
differences in biological response and identify methods to modulate
adverse biological responses.

o  Determine the mediators and inhibitors of inflammation in the TMJ
or masticatory muscles, and the mechanisms regulating their release
and action.

o  Determine the role of jaw movement and function in the maintenance
of the molecular, cellular, and morphological integrity of the TMJ.

o  Develop biological markers for diseases affecting the TMJ or
masticatory muscles.

o  Conduct studies to clarify relationships between fibromyalgia and
temporomandibular myofascial pain, to determine the natural course of
disc displacement and osteoarthritis, or to clarify the biological
effects of TMJ disc displacement on surrounding tissues.

o  Identify and characterize gender-related biological factors that
may predispose women to develop TMDs or related orofacial pain
conditions.

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 previous policies (Concerning
the Inclusion of Minorities in Study Populations), which have been in
effect since 1990.  The current policy contains some new provisions
that are substantially different from the 1990 policies.

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 reprinted in the
NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23,
Number 11.

LETTER OF INTENT

Prospective applicants are asked to submit, by September 1, 1995, 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 to which the
application responds.

Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the
information that it contains will assist in planning for the timely
review of applications.  Receipt of such letters will allow NIDR
staff to estimate the potential review workload and make review plans
that will avoid possible conflict of interest.  The NIDR staff will
provide no response to letters of intent.

The letter of intent is to be addressed to Dr. Patricia Bryant at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 9/91), available at most institutional offices of sponsored
research and may be obtained from the Office of Grants Information,
Division of Research Grants (DRG), National Institutes of Health,
5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
301-710-0267).

Applications for the FIRST (R29) Award must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST (R29) Award 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 application kit must be
affixed to the bottom of the face page of the original and the
original must be placed on top of the entire package.  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, in order to identify the application as a response to this
RFA, the RFA title "ETIOLOGY AND PATHOGENESIS OF TEMPOROMANDIBULAR
DISORDERS" and number "DE-95-002" must be typed in item 2a of the
face page of the application form and the YES box must be checked.

Specific attention should be given to efforts to contain costs and
ensure cost-competitive implementation of the project's research
goals.  Investigators also are encouraged to examine the potential
for securing supplementary funds for the project from non-NIDR
sources, such as not-for-profit and for-profit organizations.  If
additional financial support from non-NIDR sources is planned to
complement or expand the research proposed for support by the NIDR,
the applicant should explain how such activities will further the
goals of the project and make it more cost-effective.  Awardees will
be expected to update this information on an annual basis.

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.

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
6705 Rockledge Drive, Suite 1040 - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express or courier service)

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

Dr. H. George Hausch
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN-44F
45 Center Drive MSC 6402
Bethesda, MD  20892-6402

Applications must be received by October 24, 1995.  If an application
is received after that date, it will be returned to the applicant
without review.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants and responsiveness by the NIDR.
Incomplete and/or unresponsive applications will be returned without
further consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by a special emphasis
panel convened by the Scientific Review Branch, NIDR, solely to
review these applications, utilizing the review criteria stated
below.  As part of the initial merit review, a process (triage) may
be used by the initial review group in which applications will be
determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response
to the RFA.  Applications judged to be competitive will be discussed
and assigned a priority score.  Applications deemed non-competitive
will be withdrawn from further consideration; the principal
investigator/program director and the official signing for the
applicant organization will be notified of this action, after the
initial review.

Factors to be considered in the evaluation of the scientific merit of
applications will be similar to those used in the review of
traditional research project grant applications and will include: the
novelty, originality, and feasibility of the approach; the training,
experience, and research competence of the investigator(s); the
adequacy of experimental design; the accessibility and
appropriateness of study populations, study and facilities.
Secondary review of the applications will be conducted by the
National Advisory Dental Research Council.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program balance and
priorities, and the availability of funds.  Applicants also should be
aware that the total cost of the research proposed will be considered
by NIDR and ORWH staff and the National Advisory Dental Research
Council in making funding recommendations.  In circumstances in which
applications have similar scientific merit, but vary in cost-
competitiveness, the NIDR and ORWH are likely to select the more
cost-competitive application for funding.

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:

Patricia S. Bryant, Ph. D.
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN 18A
45 Center Drive MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-2095
FAX:  (301) 480-8318
Email:  BryantP@de45.NIDR.NIH.GOV

Direct inquiries regarding grants management issues to:

Ms. Theresa Ringler
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AS-55
45 Center Drive  MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800

Schedule

Letter of Intent Receipt Date:  September 1, 1995
Application Receipt Date:       October 24, 1995
Scientific Review Date:         January 1996
Advisory Council Date:          June 1996
Earliest Award Date:            September 1996

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.121.  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 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 routing 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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