Vestibular Hair Cell Regeneration

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DESCRIPTION (provided by applicant): The objective of this project is to investigate the morphological, physiological and molecular mechanisms of recovery of the horizontal crista vestibularis hair cells following surgical intraotic administration of gentamicin (GM) in the inner ear of adult chinchillas, a well known model for vestibular research. The experimental protocol is designed with the hypothesis that the effect of GM is dose and zone dependent with a threefold difference in the effective ototoxic dose, with type I hair cells being more sensitive than type II hair cells. Among type I hair cells there are also differences related to their location in different crista zones. Spontaneous regeneration of different hair cells takes place when each type is treated with doses that fall within the specific iaotrogenic ototoxic range. The specific aims include the following studies: 1) Investigation of the temporal course of damage and regeneration of the sensory cells and neurons following four pharmaco-kinetically selected doses of GM; 2) Parallel measurements of the changes in the Vestibulo Ocular Reflex (VOR) function and of single vestibular nerve fibers physiological responses to be compared with the anatomical changes; 3) Investigation of the potential protective neurotrophins effect of BDNF, FGF-2, and a combination of both in the VOR and hair cells. The anatomical and physiological changes will be evaluated in the context of a patho-physiological crista model based on anatomical and physiological principles and on the results of the preliminary studies findings. The applied techniques include histology, immunohistochemistry, fluorescence and confocal microscopy, computerized measurements with a new non-invasive animal technique of vestibule oculography for VOR function testing and electrophysiological single fiber recording methods. After more than a decade of research, the control of the anatomical and functional regeneration capacity of vestibular hair cells in mammals remains unresolved. However, our preliminary results have provided evidence of the capacity of spontaneous hair cell regeneration and the research strategies that will place us closer to the era of hair cell medical treatments for the relief of the scourge of presently untreatable diseases that cause disequilibrium and deafness. Advancing the understanding of these processes will precipitate new concepts regarding the normal function of the vestibular organs and lead to methods/treatment preventing complications associated with drugs like GM that are widely used in life saving bacterial infections on other therapeutic otological objectives as in Meniere's.