CELLULAR MECHANISMS OF OTOTOXICITY

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The primary goals of this project are to elucidate the uptake and intracellular transport pathways of aminoglycoside antibiotics in sensory hair cells and to investigate the mechanisms underlying resistance of newly regenerated hair cells to aminoglycoside toxicity. Specific aims in this proposal include: (l) Determination of the plasma membrane assembly involved in receptor-mediated endocytosis of aminoglycosides; (2) Evaluation of the role of microtubules in lysosomal targeting of aminoglycosides; (3) Evaluation of the relationship between cellular accumulation of aminoglycosides and lysosomal rupture; (4) Determination of the cellular site responsible for aminoglycoside resistance in the regenerated hair cells. Morphological measures will be obtained from both in vitro and in vivo preparations of the chick inner ear. Pharmacological reagents will be applied in in vitro preparations to selectively inhibit physiological functions of cellular organelles. Results obtained from this study will provide valuable information for a clear understanding of cellular/molecular mechanisms of aminoglycoside toxicity in the hair cells. In addition, knowledge of effective manipulation of the drug uptake pathways, if combined with powerful cellular/molecular biological techniques, would enable us to develop novel procedures for conferring mature sensory hair cells with drug resistance in the future.