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

301-435-0714.  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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