The avian inner ear is a dynamic model for studying the growth and development of excitation in auditory and vestibular hair cells. Over the past 15 years this model has produced a number of important discoveries, including ion channels, receptors, sensory cell regeneration, and more recently, stem cell behavior. The first of these, ion channels, is important in terms of their acquisition during development, since they modulate auditory and vestibular excitation. As in the visual system, excitation may """"""""sculpt"""""""" auditory pathways in the CMS. A fundamental question concerning these proteins is, what are the mechanisms that regulate their expression? The long term goals of this project are to understand the intracellular signaling pathways that regulate the expression of ion channels from a stage when sensory cells are morphologically undifferentiated to when they become hair cells. Part of this pathway is governed by interacting protein partners that in many instances also alter ion channel biophysical properties. Among these interacting partners are proteins that belong to the cytoskeleton, act as chaperones, regulate aggregation, or turn on transcription. The question to be answered in the present proposal is, what are some of the major interacting proteins that regulate ion channel expression during early and late stages of cochlear development? Thus, the proposed experiments focus on discovering and characterizing the role of such proteins in promoting the expression, function, and regional distribution of specific K+ channels in the cochlea. We and others have discovered genes that encode several K+ channels, including A-, BK, and delayed rectifier type channels. With this knowledge, the present proposal will specifically focus on the development of A- and BK channels during early and late stages of cochlear development. A-channels have a role during efferent stimulation of chick """"""""outer"""""""" hair cells, while BK channels have a role in frequency tuning.
The specific aims of the present proposal are to (1) localize and map transcript and protein expression of A- and BK channels during cochlear embryonic development, (2) characterize the function of already isolated proteins that interact with A- and BK channels during late cochlea development (3) isolate and characterize the function of proteins that interact with A- and BK channels during early cochlea development. These studies will begin to map and characterize the intracellular protein signals that regulate the formation of excitation in the peripheral auditory system. These data are relevant to understanding how these signals lead to the development and regeneration of the auditory and vestibular systems. With this knowledge we can begin to gain insights into the underlying causes of channelopathies that lead to sensori-neural deafness in children. ? ? ?
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