COCHLEAR HOMEOSTASIS

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The goal of the proposed work is to explore mechanisms of hearing loss induced by inflammatory cytokines in the cochlea. The work focused on the spiral ligament, because our recent work suggests that it 1) plays a critical role in cochlear fluid and ion homeostasis and 2) may be particularly susceptible to inflammatory processes. Type 1 fibrocytes are the most common cell type within the spiral ligament. They are part of a syncytium of cochlear supporting cells joined by intercellular connections called gap junctions. We have hypothesized that this gap junctional that this gap junctional system is essential for potassium ion recirculation from the organ of Corti to the stria vascularis and ultimately into endolymph, where a high potassium level is critical for normal high cell function. We have also found that type 1 fibrocytes contain high levels of the transcription factor NFkappaB, a protein that plays a key role in the acute phase inflammatory response of tissue to trauma or infections. In other tissues, inflammatory cytokines induced by NFkappaB can disrupt gap functional conductivity. Our working hypotheses is that inflammatory processes in the cochlea, arising from a wide array of disease states, induce cytokines in the spiral ligament, thereby blocking gap junctions between type 1 fibrocytes, depriving the stria vascularis of its potassium supply and producing profound sensorineural hearing loss. We will test this hypothesis by characterizing physiological and cytochemical responses of the cochlea following administration or induction of cytokines. We will measure changes in cochlear function by measuring evoke potentials and the endolymphatic potential and will use immunocytochemistry to document changes in cytochemical constituents of cochlear cells following the pharmacological experiments in order to determine the mechanisms underlying the cytokines' effects. The results may shed considerable light on the bases for sensorineural hearing loss in a variety of common, but poorly understood, otological disorders such as labyrinthitis, otosclerosis, genetic hearing losses involving gap junction proteins, and immune-mediated hearing loss. The proposed characterization of cytochemical substrates of inflammatory processes within the cochlea may help devise treatments or means of preventing hearing loss associated with these disorders.