Full Text DC-94-001 EARLY CELLULAR RESPONSE TO INJURY OF THE VESTIBULAR SYSTEM NIH GUIDE, Volume 23, Number 3, January 21, 1994 RFA: DC-94-001 National Institute on Deafness and Other Communication Disorders Letter of Intent Receipt Date: February 14, 1994 Application Receipt Date: March 29, 1994 PURPOSE The National Institute on Deafness and Other Communication Disorders (NIDCD) of the National Institutes of Health (NIH) invites grant applications for the support of basic studies on the molecular and cellular mechanisms subserving the early recovery process following injury to the mammalian vestibular system. An understanding of the mechanisms of this recovery will likely provide important insight into pharmacotherapeutics of vestibular disorders in humans. 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, Early Cellular Response to Injury of the Vestibular System, is related to the priority areas of Physical Activity Fitness, Unintentional Injuries, Diabetes and Chronic Disabling Diseases and Clinical Prevention Services. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-11474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-1147 3-1) through the Superintendent of Documents, Government 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 or local governments, and eligible agencies of the Federal government. Domestic applications may include international components. Applications from minority individuals and women are encouraged. MECHANISMS OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research grant (R01). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources (NCRR) may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or Principal Investigator should be included with the application. FUNDS AVAILABLE It is expected that $750,000 will be available for the first year of support (direct cost) for the entire program and that up to three applications will be funded. The level of support is dependent on the scientific merit and scope of the applications and the availability of funds. RESEARCH OBJECTIVES Background Deafferentation of one labyrinth in humans and other mammals results in a syndrome characterized by: vertigo, nausea and vomiting, spontaneous nystagmus and deficits of the gaze-stabilizing and postural reflexes. The vestibular system has a remarkable ability to compensate for injury by adaptively modifying its performance. Within the early postinjury period of two to three days, some of these symptoms and signs abate in the process of the recovery of function known as vestibular compensation. Little is known about the anatomical and physiological bases of vestibular compensation. Morphological studies of the vestibular nuclear complex (VNC) in hemilabyrinthectomized animals have revealed some acute neuronal and astrocytic alterations, but little transneuronal degeneration. Electrophysiologic studies and local glucose utilization studies of the VNC in mammalian hemilabyrinthectomized models have demonstrated the following sequence of events: an initial shutdown of the spontaneous activity of Type I neurons (by definition, neurons responding in an excitatory mode to horizontal angular acceleration) of the medial vestibular nucleus on the lesioned side, a recovery of the responsivity of these neurons, and a partial rebalancing of activity in the paired vestibular nuclei. These events occur within a time window corresponding to the onset of vestibular compensation. In mammals, this recovery of responsivity appears to be independent of transcommissural input from the contralateral (intact) labyrinth and VNC and of any remaining input from the ipsilateral vestibular nerve. Recent immunochemical studies in the rat employing the immediate early gene Fos as a metabolic activity marker of brain stem neural activation following hemilabyrinthectomy have extended these findings, demonstrating an elevation of c-fos in the VNC bilaterally during the acute recovery stage, with higher levels observed in the ipsilateral VNC. In addition, other brain stem nuclei involved in the acute recovery stage have been better defined. It has been established that a major early neural event following unilateral injury to the vestibular periphery is recovery of spontaneous activity in the VNC. However, the cellular and molecular mechanisms subserving this event remain unknown. Hypotheses invoking various modes of fast-acting alterations in the efficacy of synaptic transmission have been proposed, but have not yet been systematically tested and related to the early recovery process. Although there is evidence implicating the involvement of both excitatory amino acid (EAA) and peptide neurotransmitters in vestibular function, there have been no comprehensive studies of the neurochemical organization of the VNC and the central vestibular circuits. Several neurotransmitters (e.g., glutamate, aspartate, acetylcholine, gamma-aminobutyric acid) have been shown to modulate synaptic activity in the amphibian and mammalian VNC. One or more of these transmitters might act by mediating EAA release and/or its postsynaptic action on VNC neurons. Modification of two EAA receptor subtypes, the N-methyl-D-aspartate (NMDA) and metabotropic receptors, has been suggested as a possible mechanism for the initiation and maintenance of the events underlying vestibular compensation. Scope This initiative seeks to establish the molecular and cellular mechanisms and sites of action in the VNC and in the central vestibular circuits that follow injury of the vestibular endorgan and/or the vestibular nerve in mammalian experimental animal models. An understanding of these mechanisms will likely provide important insight into the design of pharmacotherapeutic agents that will initiate and/or accelerate the compensation process in vestibular-disordered patients. There is an urgent need for a concentrated research effort to identify the neurotransmitter, neuromodulator and second messenger substrates involved in normal vestibular function that may change during the process of neurogenic recovery underlying vestibular compensation. This research effort can be addressed by a wide spectrum of experimental methods, including, but not limited to: o direct immunohistochemical, immunoasssay and analytic biochemical methods to identify changes in the expression of specific neurotransmitter-related substrates, second messenger substrates, neurotrophic factors, metabolic activity markers and other cellular compounds associated with the recovery process; o subtractive hybridization and in situ hybridization techniques to identify specific changes in the expression of synaptic proteins and second-messenger-related RNAs during the recovery process; and, o receptor binding studies to identify changes in receptor density, phosphorylation state or other receptor properties that may modulate receptor function during the recovery process. It is very likely that recovery of vestibular function involves several receptor subclasses within the central vestibular circuits. Once the key cellular events underlying vestibular compensation are identified, drugs known to alter synaptic transmission and postsynaptic actions of the involved receptor types could be evaluated as potential therapeutic agents in the treatment of vestibular disease. LETTER OF INTENT Prospective applicants are asked to submit, by February 14, 1994, 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 otherkey 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 is helpful in planning for the review of applications. It allows NIDCD 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: Chief, Scientific Review Branch National Institute on Deafness and Other Communication Disorders Executive Plaza South, Room 400-B 6120 Executive Boulevard Rockville, Maryland 20892 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) must be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, Maryland 20892, telephone 301/710-0267; and from the NIH program administrator named below. The RFA label available in the 9/91 revision of the PHS 398 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, typewritten original of the application,including the Checklist, and five signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS National Institutes of Health Westwood Building, Room 240 5333 Westbard Avenue Bethesda, Maryland 20892 At the time of submission, two additional copies of the application must also be sent to the Chief, Scientific Review Branch, at the address listed under "Letter of Intent." Applications must be received by March 29, 1994. If an application is received after that date, it will be returned to the applicant. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG 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 by NIDCD staff for completeness and responsiveness. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NIDCD 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. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NIDCD. The second level of review will be provided by the National Deafness and Other Communication Disorders Advisory Council. Review criteria for this RFA are in general the same as those for unsolicited research grant applications: o scientific or technical merit and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o availability of resources necessary to perform the research; and o appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The anticipated date of award is July 1, 1994. An award will be made on the basis of assessment of the applications by peer review, considerations of programmatic balance, and the appropriation of allocated funds for this RFA. INQUIRIES Written and telephone inquiries concerning this RFA and request are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Daniel A. Sklare, Ph.D. Division of Communication Sciences and Disorders National Institute on Deafness and Other Communication Disorders Executive Plaza South, Room 400-C 6120 Executive Boulevard Rockville, MD 20892 Telephone: 301-496-1804 FAX: 301-402-6251 Direct inquiries regarding fiscal matters to: Sharon Hunt Grants Management Branch Division of Extramural Activities National Institute on Deafness and Other Communication Disorders Executive Plaza South, Room 400-B 6120 Executive Blvd. Rockville, MD 20892 Telephone: (301) 402-0909 FAX: 301-402-1758 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.173. Awards are 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 42CFR 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. .
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files. |