Hair cell regeneration in the avian cochlea has been found to be a common occurrence in injury from acoustic overstimulation or ototoxic drug poisoning. Regeneration leads to both a structural recovery of the sensory epithelium and a physiological recovery in auditory function. This has been a somewhat revolutionary phenomenon, for even five years ago it was thought that injury- or age- related hair cell loss led to permanent physical and functional deficits in the auditory system of higher vertebrates. Although avian hair cell regeneration is now well recognized, the identity of the precursor cells which divide and give rise to new hair cells has not been established. Moreover, the mechanisms which induce the normally quiescent precursors to re-enter the mitotic cycle have not been identified. The experiments outlined in this proposal will address the issues of what cells can act as the precursors, when the different stages of the mitotic cycle take place during the exposure and recovery periods, and when the new cells start to differentiate and express characteristics unique to hair cells. In addition to these issues, the proposed studies will examine how noise exposure causes the destruction of the tectorial membrane and what relationship this has to hair cell injury and loss. Finally, this proposal will investigate the structure and development of the hyaline cells in the chick cochlea. These cells lie on the basilar membrane just outside the sensory epithelium and, surprisingly, are innervated by efferent nerve fibers. They contain a specialized bundle of actin filaments that resemble stress fibers and anchor the hyaline cells to the basilar, membrane. Similar cells are found in the caiman cochlea and it has been proposed that they may regulate tension on the basilar membrane and, consequently, fine frequency tuning. In addition, other studies have suggested that these cells may act as precursors to the regenerating hair cells. We will conduct the proposed studies using traditional cell biological and electron microscopic techniques, but these tools will be augmented by the incorporation of new molecular biological approaches to cell function and recent advances in confocal laser scanning microscopy for high resolution imaging of fluorescent cell markers. Results from the experiments outlined in this proposal should provide insight into how regeneration is induced and regulated in the avian cochlea and how it participates in functional recovery of the auditory system. This information will hopefully stimulate investigations on the capabilities of the mammalian organ of Corti for regeneration, or at least lead to an examination of ways in which the mammalian cochlea could be artificially induced to undergo regeneration.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Hearing Research Study Section (HAR)
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Boston University
Anatomy/Cell Biology
Schools of Medicine
United States
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Cotanche, Douglas A; Kaiser, Christina L (2010) Hair cell fate decisions in cochlear development and regeneration. Hear Res 266:18-25
Kaiser, Christina L; Kamien, Andrew J; Shah, Priyanka A et al. (2009) 5-Ethynyl-2'-deoxyuridine labeling detects proliferating cells in the regenerating avian cochlea. Laryngoscope 119:1770-5
Cotanche, Douglas A (2008) Genetic and pharmacological intervention for treatment/prevention of hearing loss. J Commun Disord 41:421-43
Kaiser, Christina L; Chapman, Brittany J; Guidi, Jessica L et al. (2008) Comparison of activated caspase detection methods in the gentamicin-treated chick cochlea. Hear Res 240:1-11
Spencer, Nathaniel J; Cotanche, Douglas A; Klapperich, Catherine M (2008) Peptide- and collagen-based hydrogel substrates for in vitro culture of chick cochleae. Biomaterials 29:1028-42
Parker, Mark A; Corliss, Deborah A; Gray, Brianna et al. (2007) Neural stem cells injected into the sound-damaged cochlea migrate throughout the cochlea and express markers of hair cells, supporting cells, and spiral ganglion cells. Hear Res 232:29-43
Dai, C F; Mangiardi, D; Cotanche, D A et al. (2006) Uptake of fluorescent gentamicin by vertebrate sensory cells in vivo. Hear Res 213:64-78
Duncan, Luke J; Mangiardi, Dominic A; Matsui, Jonathan I et al. (2006) Differential expression of unconventional myosins in apoptotic and regenerating chick hair cells confirms two regeneration mechanisms. J Comp Neurol 499:691-701
Morest, D Kent; Cotanche, Douglas A (2004) Regeneration of the inner ear as a model of neural plasticity. J Neurosci Res 78:455-60
Mangiardi, Dominic A; McLaughlin-Williamson, Katherine; May, Kara E et al. (2004) Progression of hair cell ejection and molecular markers of apoptosis in the avian cochlea following gentamicin treatment. J Comp Neurol 475:1-18

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