PROTEINS OF THE ORGAN OF CORTI

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The mammalian auditory system-- unrivaled in sensitivity and frequency discrimination -- is susceptible to a host of afflictions that compromise acoustic performance. The key to the prevention or cure of hearing disorders resides in a thorough knowledge of auditory transduction and transmission. Despite rapid advances in our understanding of the mechanico-electrical aspects of auditory function, our appreciation of the underlying macromolecular mechanisms remains fragmentary. Although the cells of the mammalian auditory organ, the organ of Corti (OC), express thousands of proteins, a small minority are directly associated with the transduction/transmission processes. Detailed characterization of these molecular auditory components will furnish substantial insight into auditory function. OCP1 and OCP2 -- expressed specifically and abundantly in the OC -- are members of this elite subset. On the microscale, OCP2 is expressed in a pattern that exactly mirrors the epithelial gap junction system of the cochlea. Whether this intriguing anatomical association has functional significance, or whether it is merely coincidental, is uncertain. The available evidence suggests that OCP1 and OCP2 are subunits of vital multi-protein regulatory complexes, conceivably the same complex. The identification of additional subunits is the immediate project objective. The OCPs -- i.e., OCP1, OCP2, and their associated polypeptides -- will then be subjected to a battery of biochemical, molecular biological, physical, and morphological techniques. Sequence information, derived from the cloned cDNAs, will reveal potential sites for post-translational modification and potential ligand-binding motifs. Functionality of these structural features will be assessed biochemically. Recombinant OCPs will be investigated by analytical ultracentrifugation, optical spectroscopy (fluorescence and circular dichroism), microcalorimetry, and NMR spectroscopy. Expression of the OCPs at the mRNA and protein levels will be examined as a function of age and development in the guinea pig, rat, and gerbil, and in OC- derived cell lines. Alterations in expression will also be monitored in OC-derived cell lines in response to environmental perturbations and following transfection with sense- and anti-sense constructions of the OCP cDNAs. The OCPs are likely targets of auditory dysfunction -- either inherited or acquired. In fact, the location of the Ocp2 gene is identical to that of DFNAl, a familial postlingual deafness disorder.