MECHANOTRANSDUCTION IN THE VESTIBULAR LABYRINTH NIH GUIDE, Volume 22, Number 42, November 19, 1993 PA NUMBER: PA-94-013 P.T. 34 Keywords: Communicative Disorders, Hearing Biomechanics Electrophysiology National Institute on Deafness and Other Communication Disorders 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 of mechanotransduction in the vestibular labyrinth. It is expected that research in this area will advance our understanding of the mechanisms of vestibular dysfunction arising from disease of the inner ear. 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 program announcement (PA), Mechanotransduction in the Vestibular Labyrinth, is related to the priority areas of physical activity fitness, unintentional injuries, occupational safety and health, 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. 017-001-11473-1) 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. Foreign institutions are not eligible to apply for the First Independent Research Support and Transition (FIRST) (R29) award. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The mechanisms available for support of this program are the NIH individual research project grant (R01) and the FIRST (R29) award. 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. If so, a letter of agreement from either the GCRC program director or Principal Investigator should be included with the application. RESEARCH OBJECTIVES In vestibular transduction, an adequate physical stimulus results in a displacement of the endorgan accessory structures, the cupula and the otolithic membrane, overlying the vestibular hair cells, deflecting the hair bundles of the latter. The deflection of a hair cell's bundle towards its tallest stereocilia opens specialized transduction channels in the stereocilia. This increases the flow of positive ions into the hair cell, leading to calcium entry and the release of neurotransmitter to afferent fibers synapsing with the hair cell. Research on vestibular mechanotransduction may be conducted at three levels: (1) macromechanics- the motion, deformation and coupling of the endorgan accessory structures in relation to the vestibular receptor organs; (2) micromechanics- the motion, deformation and coupling of sensory hair bundles in relation to the overlying accessory structures; and (3) the internal mechanics of ciliary bundles. This initiative seeks to encourage research on the mechanical and molecular aspects of the vestibular transduction process at these three levels in animal models and/or computer simulation models. Based on the early pioneering work of Steinhausen and others, it has been thought that the macromechanics of the semicircular canals could be modeled as a pendulum moving in a viscous medium. On the basis of this model, cupular displacement in the frequency range of physiologic head movement is proportional to angular velocity. Along the same lines, the otolithic organs have been described as uniform structures with the mechanical behavior of an overdamped, second-order system whose displacement is proportional to applied linear force. These models have shaped the field of vestibular physiology for many years. Indeed, any discrepancies from the models' predictions and the observed response dynamics of afferent discharge have been assumed to result from filtering by later stages of the transduction process. Recent experimental observations, however, have cast considerable doubt on the validity of these models. In vivo experimental observations suggest that the cupula is deformed like a diaphragm while adhering firmly to the ampular wall during physiologic stimulation. The otolithic organs have been shown to have complex curved surfaces appropriately modeled as a viscoelastic material. The development of enhanced video microscopy and other imaging techniques provide new opportunities to describe cupular and otolithic motion more accurately. Recent anatomic and electrophysiologic studies of the bullfrog utricular macula have identified four categories of type II hair cells with hair bundle morphologies that differ systematically with macular location. These bundle categories have, in turn, been correlated with afferent function. More regional mapping studies of hair bundle morphology and mechanics are needed. In particular, it is important to determine whether regional variations in micromechanics underlie afferent response diversity. Contemporary imaging techniques offer the opportunity to visualize simultaneously the displacement, deformation and coupling of the hair bundles and the accessory structures. The prevailing view that the mechanics of the vestibular end organs are entirely determined by their passive mechanical properties has recently been challenged by two important findings: (1) motile responses in vestibular hair cells; and, (2) the influence of adaptation of the mechanoelectric transducer channel on hair bundle stiffness. The shortening of isolated mammalian type I vestibular hair cells has been demonstrated following exposure to a potassium-rich medium. In addition, voltage-dependent active hair bundle motions have been observed in mechanically displaced saccular hair cells. If present in vivo, hair cell motility might directly influence the mechanosensitivity of the vestibular receptor organs. Neurotransmission in auditory, vestibular and lateral line systems is triggered by a series of events that follow the opening of mechanically sensitive transduction channels in the hair cell stereocilia. Evidence has accumulated suggesting that the opening of a channel results from increased mechanical tension on the channel protein imposed by fine filaments (tip links) linking each adjacent taller stereocilium in a hair bundle. An adaptation mechanism, dynamically modulating transducer currents and afferent response by adjustments in the tension of these tip links, has been postulated on the basis of observations in some isolated amphibian vestibular hair cells. Whenever possible, the functional significance of experimental observations and the validity of models of vestibular mechanotransduction should be established by relating these events to consequent neural function. Research studies may include, but are not limited to, the topics listed below: o application of advanced imaging techniques to describe vestibular mechanics in situ; o development of in vitro epithelial preparations for studies of labyrinthine mechanics; o development of data-driven models of vestibular mechanics; o determination of the micromechanics of the different vestibular receptor subtypes, type I and type II hair cells; o determination of the role of regional variations of vestibular micromechanics in afferent response diversity; o determination of the role of the internal mechanics of the ciliary bundles in vestibular mechanotransduction; o determination of the role of active hair cell processes in vestibular mechanotransduction. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the standard application deadlines as indicated in the application kit. The receipt dates for applications for AIDS-related research are found in the PHS 398 instructions. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301-710-0267. The title and number of the announcement must be typed in Section 2a on the face page of the application. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by the appropriate national advisory council. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to that ICD. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program balance among research areas of the announcement INQUIRIES Written and telephone inquiries concerning this PA 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 Division of Extramural Activities National Institute on Deafness and Other Communication Disorders Executive Plaza South, Room 400-B 6120 Executive Boulevard 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 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. .
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