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REQUEST FOR APPLICATIONS FOR A
CONTRACT
Subject: Development and Validation of a Behavioral
Animal Model of Emotional or Autonomic Reactions to
Tinnitus
Source: Tinnitus Research Consortium
Letter of Intent Receipt Date: December 15,
2009
Proposal Receipt Date: February 1, 2010
PURPOSE
The Tinnitus Research Consortium, supported by
private philanthropy, invites proposals for the
development and validation of a behavioral animal
model of emotional or autonomic reactions to
tinnitus. The goal of this request for proposals
is to produce an animal model in which tinnitus can
be verified behaviorally and in which emotional or
autonomic reactions to the tinnitus can be
demonstrated and measured.
ELIGIBILITY REQUIREMENTS
Proposals may be submitted by domestic (US)
for-profit and non-profit organizations, such as
universities, colleges, hospitals, clinics,
laboratories and units of state and local
governments.
SUPPORT
The total project period for a proposal
submitted in response to this request may not
exceed three years. There are no plans for
continuation of the project beyond three years.
Responsibility for planning, direction and
execution of the proposed project will rest solely
with the proposer. The total funds planned for
support of the successful response to this request
for proposals are $300,000. An award of up to
$100,000 per year may be made for direct costs of
the project. In contracts with investigators, the
Tinnitus Research Consortium does not provide
overhead expenses. An award made pursuant to this
request for proposals is contingent upon the
availability of funds for this purpose. The award
will be made on or about June 1, 2010, and the
starting date should be July 1, 2010 or later.
The Tinnitus Research Consortium advocates
prompt reporting of the results of research
projects supported by it at scientific meetings and
in peer-reviewed journals without exception or
contingency. The grantee and grantee institution
may not enter into any agreement with a third party
regarding the research project or its results
without written permission of the Tinnitus Research
Consortium.
STATEMENT OF WORK
1. Background
Tinnitus is the perception of a sound in the
absence of an environmental acoustic stimulus.
Approximately 30 million people in the United
States experience tinnitus, and probably three
million of these individuals suffer from tinnitus
to the extent that it interferes substantially with
the activities of daily living including sleep.
Tinnitus is a symptom that is associated with
virtually all diseases and disorders affecting the
auditory system and can arise from a lesion in any
part of the auditory system. The site(s) of
generation of the sound percept may be in the
central nervous system even if the initial lesion
is in the end organ of the auditory system. The
most common percept of tinnitus is thought to
result from anomalous activity in and perhaps
reorganization of parts of the central auditory
pathways after injury to the peripheral part of the
auditory system.
Animal perceptual models of tinnitus developed
over the last 20 years are based on the assumption
that animals trained to respond in a particular way
during silent intervals will respond differently
when they perceive some sound in the place of
silence. If such differences in patterns of
responding are observed following interventions
expected to produce tinnitus, the assumption is
made that the change in responding is the result of
the tinnitus. Subsequently developed animal models
of tinnitus, relying, e.g., on active avoidance,
identification of the direction of the perceived
source of tinnitus or poorer detection of silent
gaps in noise similar to their tinnitus, are more
rapidly achieved and less labor intensive and lend
themselves to the verification of chronic as well
as acute tinnitus.
From studies in animal models of tinnitus, there
is increasing evidence that a neural correlate of
tinnitus is a change in the pattern of spontaneous
activity in some of the centers of the central
auditory pathway. Similarly, imaging studies in
humans have suggested sites of neural activity
related to tinnitus that include the dorsal
cochlear nucleus, inferior colliculus, thalamus and
auditory cortex.
A confounding aspect of the experimental
induction of tinnitus is the occurrence of hearing
loss. The experimental manipulation causing the
hearing loss may or may not cause tinnitus. In
animal studies, segregation of the correlates of
tinnitus from the consequences of hearing loss
requires the inclusion of a second control group:
animals that have been subjected to the
manipulation for the induction of tinnitus, e.g.,
intense sound exposure, and show a hearing loss but
do not show behavioral evidence of tinnitus.
Comparison of normal animals, animals with hearing
loss without tinnitus and animals with hearing loss
and tinnitus is required for the interpretation of
the results and for the research to have value.
Interest is increasing in the emotional and
autonomic reactions to tinnitus. In humans, the
negative reactions to tinnitus occur less
frequently than the perception of tinnitus and are
considered to be based at least in part on
cognition. The negative reactions to tinnitus
correlate more directly with tinnitus annoyance
than with the pitch or loudness of the percept of
tinnitus. The reactions to tinnitus are thought to
result from changes in the parts of the limbic
system involved in the evaluation of the emotional
content of sensory experiences and in the
sympathetic part of the autonomic nervous system.
Limited imaging evidence of limbic system
involvement has been found with certain forms of
tinnitus. Emotional distress, depression and
insomnia associated with tinnitus may have a common
basis in some limbic structure such as the nucleus
accumbens. Autonomic responses such as
tachycardia, arrhythmia, hypertension, smooth
muscle spasm and musculoskeletal tremor have been
characterized as a form of stress in some early
animal models of tinnitus.
Stress induction, administration of psychotropic
agents or fear conditioning could serve as the
basis for animal models for the study of reactions
to tinnitus. Stress, as, for example, induced by
body restraint, has been measured with blood
glucocorticosteroid levels. Also, the use of
benzodiazepine receptor inverse agonists may
produce anxiety. Additionally, fear conditioning
has been induced in animals principally with sound
as the conditioned stimulus. Such animal models of
conditioned or contextual fear may be applicable to
research on the reactions to tinnitus perhaps
mediated through the amygdala. Thus, it may be
possible to modify animal models of tinnitus with
the introduction of stress, administration of
benzodiazepine receptor inverse agonists or
achievement of conditioned fear to sound or
contextual fear. Or alternatively, it may be
possible to modify animal models of stress,
administration of benzodiazepine receptor inverse
agonists or conditioned or contextual fear by the
introduction of tinnitus. In creative combinations
of these models, perception of tinnitus may be
verified behaviorally whereas emotions, such as
anxiety, depression or insomnia, or autonomic
responses, such as tachycardia, hypertension,
smooth muscle spasm or musculoskeletal tremor,
resulting from the perception of tinnitus may be
demonstrated and measured. It may be possible to
produce simultaneously an animal model that
exhibits tinnitus and stress to or fear of
tinnitus.
2. Objectives
The principal objective of this work is to
develop and validate a behavioral animal model that
demonstrates negative reactions to tinnitus so that
structural and functional substrates underlying the
reactions to tinnitus can be studied.
Demonstration of reactions to tinnitus and
measurement of those reactions will permit the
systematic experimental manipulations of those
reactions and the introduction of drugs as well as
other therapeutic interventions to modify or
extinguish the reactions to tinnitus even if the
percept of tinnitus cannot be eliminated.
The work to be supported in response to this
request must be clearly relevant to progress in the
scientific problems of negative reactions to
tinnitus. The tinnitus must be behaviorally
verified. The negative reactions must be clearly
associated with the perception of tinnitus. A
means of measuring the reactions to tinnitus must
be developed and validated.
3. Work to Be Performed
The proposal should contain a creative design of
the combination of an animal model displaying an
emotional reaction or autonomic response to
tinnitus and a behavioral model of tinnitus.
For an example, the work could proceed with the
following strategy:
A. First, produce or obtain and validate a
behavioral animal model of tinnitus that relies on
poorer detection of silent gaps in noise (pre-pulse
inhibition [PPI] of the acoustic startle
reflex evoked by silent gaps) and provides chronic
reduced detection of or reduced PPI to silent gaps
in noise.
B. Second, produce or obtain and validate a
behavioral animal model of fear in the same species
that demonstrates anxiety or other emotional
behavior or tachycardia, hypertension, smooth
muscle spasm, musculoskeletal tremor or other
sympathetic response to fear.
C. Then, induce tinnitus and fear of the percept
of tinnitus in an animal model and validate that
the reaction to fear results from the presence of
tinnitus.
The proposal should include, but not be limited
to:
- description of the strategies to be followed
and the anticipated results;
- experimental model to be utilized and why it
was selected, including methods for the
induction of tinnitus, methods for behaviorally
verifying the presence of tinnitus, methods for
producing stress, anxiety or fear in the
species, methods for demonstrating the
reaction(s) to stress, anxiety or fear, methods
for inducing stress or anxiety to or fear of the
percept of tinnitus, methods for demonstrating
the reaction(s) to the tinnitus, methods for
confirming the association of the reaction(s) to
the tinnitus and methods for measuring the
reaction(s) to tinnitus;
- strategies for validation of the methods for
confirming the association of the reaction(s) to
the percept of tinnitus and methods for
measuring the reaction(s) to tinnitus;
- timetable for the achievement of key aspects
of the project;
- control of variables known to influence the
results;
- control experiments to validate the
observations;
- statistical management of the data; and
- alternative plans for unanticipated
results.
SPECIAL REQUIREMENTS
The principal investigator must obtain the
approval of his or her Institutional Animal Care
and Use Committee for the project and provide
documentation of the approval. Semiannual progress
reports and annual financial reports are required,
and the principal investigator is expected to
correspond or meet quarterly with the
representative of the Tinnitus Research Consortium
to review progress toward the key aspects of the
project and plans for the next several months. In
addition, the principal investigator is expected to
meet with the Tinnitus Research Consortium at the
initiation of the project and annually to discuss
the progress and direction of the project. Funding
for the second and third years is contingent on
evidence of satisfactory progress in the semiannual
progress reports. A final progress report is
required at the end of the contract period.
LETTER OF INTENT
The Tinnitus Research Consortium will contact
and discuss the requirements for this work with
investigators whom it judges to be capable of
achieving these challenging objectives.
Nevertheless, this competition is open to all
proposers, and every effort will be made to carry
out unbiased evaluation of the submitted proposals
and award and negotiation of this contract.
Prospective proposers are requested to submit by
December 1, 2009 a letter of intent containing the
title of the proposed research; a five-page
précis of the proposal; name, address,
e-mail address and telephone and fax numbers of the
principal investigator; and the names of other key
personnel and the participating institution(s).
Representatives of the Tinnitus Research Consortium
will meet or correspond with qualified proposers
early in December 2009 to counsel proposers
regarding the specific requirements relative to
their proposals to be competitive for this award.
The letter of intent should be sent to: James B.
Snow, Jr., M.D., Tinnitus Research Consortium, 327
Greenbriar Lane, West Grove, PA 19390-9490 or
e-mail jandssnow@comcast.net.
PROPOSAL PROCEDURES
The proposal form and a list of the members of
the Tinnitus Research Consortium may be obtained
from James B. Snow, Jr., M.D., Tinnitus Research
Consortium, 327 Greenbriar Lane, West Grove, PA
19390-9490, telephone and fax 610-345-0085 and
e-mail jandssnow@comcast.net.
Please submit the proposal in electronic format in
a single Word file on a CD and a signed printed
version and three signed copies to James B. Snow,
Jr., M.D., Tinnitus Research Consortium, 327
Greenbriar Lane, West Grove, PA 19390-9490 by
February 1, 2010.
REVIEW CONSIDERATIONS
Proposals will be evaluated for scientific and
technical merit by experts in the subject matter of
the project selected by the Tinnitus Research
Consortium and receive an evaluation score. A
second level of review will be provided by the
Tinnitus Research Consortium, which will make
funding recommendations to the sponsor.
Evaluation Criteria
A carefully designed and feasible study that
attempts to develop and validate a behavioral
animal model of the emotional or autonomic
reactions to tinnitus will be considered responsive
to this request for proposals.
Additional evaluation criteria include:
- scientific and technical significance and
originality of the proposed research;
- appropriateness and adequacy of the design
of the study and the methods to be employed; in
particular, the design of the study should
permit differentiation between the effects of
tinnitus and the effects of hearing loss and
other consequences of the experimental
manipulations;
- ability to correlate individual subject data
as well as group data with perception of and
reactions to tinnitus;
- availability of pilot data of the procedures
to be used;
- qualifications and research experience of
the principal investigator and key staff for the
proposed project;
- availability of laboratory and animal
facilities necessary to perform the work;
- rationale for selection of the experimental
model to be studied;
- provisions for the protection of the welfare
of the animal subjects and safety of the
research environment;
- appropriateness of the plan for the
statistical management of the data; and
- appropriateness of the budget and the
duration of the proposed project.
Special consideration will be given to proposers
who are successful in obtaining partial support for
the project from other sources.
INQUIRIES
Postal mail, telephone or e-mail inquiries
regarding this request for proposals are
encouraged. The opportunity to clarify any issues
for potential proposers is welcomed. Direct
inquiries to James B. Snow, Jr., M.D., Tinnitus
Research Consortium, 327 Greenbriar Lane, West
Grove, PA 19390-9490, telephone and fax
610-345-0085 and e-mail jandssnow@comcast.net.
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