This proposal will investigate gene transfer and cell death in the cochlea. Gene transfer has recently become an important method for tissue engineering for experimental and clinical purposes. The experimental field of inner ear biology and the otology clinic may benefit greatly from gene transfer technology. Viral vectors have become the vehicle of choice for in vivo genetic interventions in the nervous system. The cochlea may be among the organs that can benefit from genetic manipulation via viral vectors. We have demonstrated efficient infection of guinea pig spiral ganglion cells in vitro and in vivo with the Ad.RSVntlacZ adenoviral vector. Transgene expression has been detected as long as eight weeks after the inoculation. In this application we propose to continue our successful preliminary experiments to optimize variable parameters of adenoviral mediated gene transfer into cochlear cells. Specifically, we will (a) determine the optimal inoculation parameters needed for efficient infection of spiral ganglion cells, (b) characterize the immune response to the viral infection, (c) determine the duration of viral gene expression, (d) characterize the spread of infection to adjacent tissues, and (e) determine the functionality of infected spiral ganglion cells using ABR measurements. We also propose to determine the effects of gene transfer on spiral ganglion cell survival. Specifically, we will determine if it is possible to (a) rescue spiral ganglion cells by overexpressing bcl-2 and (b) induce cell death in spiral ganglion cells by viral-mediated overexpression of bcl-xs. The data we have been generating, along with the experiments we now propose will solidify the foundation of viral mediated gene transfer in the cochlea. This technology will facilitate experimental elimination of specific cell types in the cochlea, and create a powerful tool for physiological studies in this organ. As such, it will be of benefit to the other projects described in our Program Project. Moreover, gene transfer will enable to study function of specific genes in the ear. It will also help the important clinical goal of preserving spiral ganglion cells, for reducing progressive trauma and enhancing benefits from cochlear implants.

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University of Michigan Ann Arbor
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Stefanescu, Roxana A; Koehler, Seth D; Shore, Susan E (2015) Stimulus-timing-dependent modifications of rate-level functions in animals with and without tinnitus. J Neurophysiol 113:956-70
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