This research proposal is specifically designed to clarify the role that members of the nerve growth factor (NGF) family of neurotrophins and their receptors play in the development of the peripheral auditory system, and to define their mode of action in the mediation of neuron-target tissue interactions during the development of this sensory system. We propose to study the relationship between the NGF family of neuronotrophins (i.e. NGF, BDNF, NT-3 and NT4) and the development of the auditory system (i.e. neuron-sensory hair cell interaction) at both cell and molecular biological levels. The in vivo approach of this study will employ in situ hybridization with labelled cRNA and oligonucleotide probes to detect sites of gene expression for the neurotrophins and their receptors. In vitro we will test the neuronotrophic effects of these growth factors on developing auditory neurons and then the consequences of decreased or stopped production of these neurotrophins on auditory development. Another set of in vitro experiments will explore the consequences of inserting the genes that encode NGF and/or its high affinity receptor (i.e. trk-A, protooncogene) on neuron-sensory ha?? cell interaction during auditory development. Three hypotheses are proposed as specific aims and will be tested by the five experiments described in this proposal.
Specific Aim 1 is to test the hypothesis that members of the NGF family of neurotrophins and their receptors are expressed in vivo during the development of the auditory system.
Specific Aim 2 is to test the hypothesis that auditory neurons respond to the neuronotrophic effects of members of the NGF family of neurotrophins during development, and that their sensitivity and response to these neuronotrophic growth factors changes during development.
Specific Aim 3 is to test the hypothesis that changes in the normal levels of production or availability of members of the NGF family of neurotrophins or their receptors will alter one or more of the following phenomena: a) neuritic ingrowth to the developing auditory receptor, b) stability of peripheral, afferent auditory neuritic projections and c) survival of afferent auditory neurons. Understanding of the exact nature of these interactions may open new pharmacological prospects (e.g. growth factor therapy) with regards to the restoration of hearing function following a lesion affecting the cochlea.
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