The plasma membrane of the cell plays an essential role in the maintenance of cellular homeostasis. It is also the first site in transferring a mechanical force into the hair cell. While strong evidence has implicated membrane disruption as an early event of hair cell degeneration in noise-induced cochlear trauma, it is unclear how such damage contributes to the pathogenesis of acute hair cell death. Our long-term goal is to better understand the biological and molecular mechanisms of noise-induced hearing loss. The objective of this research is to determine the role of membrane disruption in the generation of acute hair cell death. The central hypothesis for the proposed research is that membrane dysfunction is involved in the regulation of acute hair cell apoptosis. We plan to test our central hypothesis by examining two essential functions of the plasma membrane, membrane barrier and membrane adhesion. Specifically, the following three aims will be addressed: (1) to determine the role of membrane permeabilization in the regulation of acute hair cell death and evaluate the effect of a membrane repair strategy on the hair cell's response to mechanical stress, (2) to determine the effect of the disruption of membrane adhesion on the cytoskeletal structure of apoptotic hair cells, and (3) to identify the apoptosis-related molecules that are involved in the generation of acute cochlear damage. Our contribution here is expected to increase understanding of the regulatory mechanism of acute hair cell apoptosis. This contribution is significant because the new insights into acute membrane dysfunction fill the knowledge gap between direct mechanical stress and subsequent signal transduction leading to cell death. Importantly, controlling the membrane events of apoptosis may lead to the development of novel pharmacological strategies for suppression of acute hair cell death.
Noise-induced hearing loss is the most common cause of acquired hearing loss among those under the age of 40 and ranks among the top 10 disabilities among military personnel. The proposed study will investigate the role of plasma membrane dysfunction in the regulation of acute hair cell death induced by exposure to intense noise. From a clinical perspective, better understanding of the biological mechanisms of noise-induced sensory cell death can greatly enhance our ability to explore novel therapeutic strategies for reduction of noise-induced hearing loss.
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