This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Auditory hair cells are the sensory cells that transduce acoustical signals into neural ones in vertebrates, thus providing the ability to hear. In mammals, when these terminally-differentiated cells are damaged or lost, the result is permanent loss of hearing since lost mammalian hair cells do not regenerate. In fish and birds, damaged auditory sensory epithelia have the capability of regenerating new hair cells, resulting in recovery of hearing. Recent studies show that goldfish exhibit both structural (hair cells) and functional (hearing) recovery following noise exposure. To fully understand what normal cellular processes lead to regeneration in fishes, knowledge of how specific genes mediate hair cell growth (proliferation and transdifferentiation) is essential. The overall goal of this project is to study the process of hair cell regeneration in zebrafish, since zebrafish has become a productive model for studying the gene expression of many cellular pathways. The current proposal has three aims directed at this goal: 1) to determine the time course of hair cell death and regeneration in noise-exposed zebrafish (using immunocytochemistry);2) to determine the time course of functional recovery of hearing following noise exposure in zebrafish (using auditory brainstem response);and 3) to examine gene expression during the process of hair cell death and regeneration in the zebrafish ear using rtPCR and microarray analysis. We were initially interested in examining expression of three genes (p27Kip1, Atoh1, and Rb1). These genes have recently been shown to regulate hair cell development in mammals. We have performed a microarray experiment that examined gene expression during the process of hair cell generation, and the three genes of interest above were not highly regulated, but growth hormone and a number of other genes were. We recently validated our microarray experiments with real-time PCR using significantly regulated genes. These studies will provide a basis for future investigations in hair cell regeneration research and may be critical in establishing a link between hair cell proliferation and development of new therapeutics to treat deafness.
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