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 301/435-0714; 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.

.

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