PA-01-108: NEW APPROACHES TO THE PATHOGENESIS AND TREATMENT OF OROFACIAL PAIN

Department of Health
and Human Services (HHS)

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This Program Announcement expires on June 30, 2004, unless reissued. NEW APPROACHES TO THE PATHOGENESIS AND TREATMENT OF OROFACIAL PAIN Release Date: June 6, 2001 PA NUMBER: PA-01-108 National Institute of Dental and Craniofacial Research Office of Research on Women’s Health THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Institute of Dental and Craniofacial Research (NIDCR) and the Office of Research on Women’s Health (ORWH) invite research grant applications for innovative basic research investigations to study the pathogenesis of orofacial pain, in particular temporomandibular disorders (TMDs). A broad range of research proposals on pathogenic mechanisms, new animal models, and interventions to halt and reverse disease processes is encouraged. The NIDCR and the ORWH encourage collaborative projects that bring together investigators from all relevant scientific disciplines including molecular and cellular biology, immunology, endocrinology, biochemistry, pathology, and chemistry interested in studying this problem. Applications that include collaboration with foreign scientists conducting unique research on this topic are also encouraged. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA addresses the priority areas of dental, oral and craniofacial health. Potential applicants may obtain a copy of "Healthy People 2010" (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 or local governments, and eligible agencies of the Federal government. The total requested project period for an application submitted in response to the PA may not exceed five years. Domestic applications may include international components but these components. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The mechanism of support for this PA is the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. New investigators without prior R29 or R01 support are strongly encouraged to apply. They should identify their status on the cover page for the application. In addition, the research topics in bioengineering that are of special interest to the NIDCR are identified in the NIH Omnibus Solicitation for SBIR/STTR Grant Applications found at: http://grants.nih.gov/grants/funding/sbir.htm - sbir Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant Applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm Applications requesting less than $250,000 per year in direct costs must use the modular format, with funds requested in $25,000 direct cost modules. A feature of the modular grant is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information is required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Applications that request more than $250,000 in any year must use the standard PHS 398 (rev 4/98) application instructions. RESEARCH OBJECTIVES Orofacial pain, in particular disorders of the TMJ, represent a group of conditions that affect at least 10 million people, primarily women, in the United States. These disorders are therefore an important national health problem, affecting many people to the point that many normal occupational and social activities are precluded. The major clinical manifestations of TMDs are orofacial pain and tenderness localized (at least initially) to the masticatory muscles and/or the TMJ. The vast majority of attempts to treat TMDs have focused on dental approaches to the problem, with relatively few studies utilizing state-of-the-art approaches to the pharmacological or non-pharmacological management of joint or muscle pain. The appropriate treatment of chronic pain has received much attention, with practice guidelines published by the World Health Organization, U.S. Agency for Health Care Policy and Research, and more recently the Joint Commission on Accreditation of Healthcare Organizations. Despite this, there is considerable evidence that patients with all forms of chronic pain are under treated, and are typically given inappropriate regimens of pain-relieving drugs. TMDs are no exception to this, with few published studies examining appropriate pharmacological ladders of agents. One of the dangerous consequences of a failure to effectively treat acute pain is that it can evolve into chronic pain that may have a central origin. This is thought to be due to the induction of neuroplastic changes in central nervous system structures induced by a continuous afferent barrage. Basic research in models of pain is revealing molecular and cellular mechanisms that may provide a basis for the continued perception of pain, even when the initiating insult has resolved. These effects appear to result in the maintenance of functional changes in central nervous system neuronal hyperexcitability. For example, recent studies of neurochemical mechanisms in pain models that produce hyperalgesia suggest that suppression of nor-adrenergic activity is associated with this effect. This is consistent with clinical findings that central administration of alpha-adrenergic agents is effective in the treatment of opioid resistant pain. Summary Areas of research responsive to the PA include physiological and molecular mechanisms relevant to pain in the orofacial region, as well as pharmacological approaches to the treatment of orofacial pain, especially TMDs. The list below is not meant to be exhaustive, exclusive, or delimiting, rather these merely represent illustrations of projects that would be considered relevant to this PA. Examples of specific research topics include: o animal models of specific pathophysiologic conditions that produce orofacial pain, in particular ones that induce temporomandibular dysfunction, o genetic predisposition as a factor in differential responses to insults that produce orofacial pain and TMDs, o defining unique molecular or physiological differences in the components of the orofacial region that may be relevant to orofacial pain syndromes, o development and use of biological markers and surrogate end points to objectively classify types of orofacial pain, and for use in the development of new therapeutic strategies, o peripheral and central sensitization of nociceptors, in particular as it relates to stimuli or lesions known to induce orofacial pain, o state of the art analgesic approaches for alleviation of orofacial pain, o the design and development of controlled release delivery systems for delivery of both conventional and new drugs at targeted specific sites of the TMJ to alleviate pain and inflammation, 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 sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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. 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://grants.nih.gov/grants/guide/notice-files/not98-024.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. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. APPLICATION PROCEDURES Applications are to be submitted on grant application form PHS 398 (rev. 4/98). 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, Phone (301) 710-0267, Email: GRANTSINFO@NIH.GOV. Applications are also available on the internet at http://grants.nih.gov/grants/funding/phs398/phs398.html. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that they must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, applicants must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, applicants must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires applicants to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at: http://grants.nih.gov/grants/guide/notice-files/not98-030.html 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. Submit a signed, typewritten, original of the application, including the checklist and five signed photocopies in one package 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) SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 in direct costs in any year must follow the traditional PHS 398 application instructions). The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD For applications requesting less than $250,000 in Direct Costs per year, do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - For applications requesting less than $250,000 in Direct Costs per year, do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION If you are using the modular budget format, prepare a Modular Grant Budget Narrative page (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. All other applications follow the standard PHS 398 instructions. o UNDER PERSONNEL, List all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. o FOR CONSORTIUM/CONTRACTUAL COSTS, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. o Provide an additional narrative budget justification for any variation in the number of modules requested. BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. REVIEW CONSIDERATIONS Upon receipt, the NIH Center for Scientific Review (CSR) will review applications for completeness. An appropriate peer review group convened in accordance with NIH peer review procedures will evaluate applications that are complete for scientific and technical merit. As part of the 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 would be discussed, assigned a priority score, and receive a second level review by an appropriate advisory council. 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 comments, reviewers will be asked to discuss the following of the application in order to judge the likelihood that the proposed of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. Significance. 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? Approach. Are the conceptual framework, design and methods adequately developed, well integrated, and appropriate to the aims of the project? Does applicant acknowledge potential problem areas and consider alternative tactics? 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? Investigators. Are the investigators 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 partners? Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed collaborative arrangements take advantage of unique features of the scientific environment? Is there evidence of collaborative institutional support? The initial review group will also examine: the appropriateness of proposed project budget and duration, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Factors that will be used to make award decisions are as follows: o Scientific and technical merit of the proposed project as determined by peer review, o Cost effectiveness of the proposed strategy, o Promise of the proposed program to accomplish the goals of this PA and address the needs of the participating Institute and Center as regards their interest in pain research, o Program priorities and program balance, o Availability of funds. INQUIRIES Written, email and telephone inquiries are encouraged early in the development of the application. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Kenneth A. Gruber Chief, Chronic Diseases Branch Division of Extramural Research National Institute of Dental and Craniofacial Research Natcher Building, Room 4AN-18C Bethesda, MD 20892-6402 Telephone: (301) 594-4836 FAX: (301) 480-8318 Email: Kenneth.Gruber@nih.gov Dr. Lisa Begg. Director of Research Programs, Office of Research on Women’s Health National Institutes of Health Building 1, Room 201 Bethesda, MD 20892 Telephone: (301) 402-1770 FAX: (301) 402-1770 Email: :beggl@od.nih.gov Direct inquiries regarding fiscal matters to: Mr. Martin Rubinstein Office of Grants Management National Institute of Dental and Craniofacial Research Natcher Building, Room 4AN-44A Bethesda, MD 20892-6402 Telephone: (301) 594-4800 FAX: (301) 480-8301 Email: Martin.Rubinstein@nih.gov 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 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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