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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