Noise-induced acute hair cell Death

描述（由申请人提供）：细胞的质膜在维持细胞稳态中起着至关重要的作用。它也是第一个将机械力传递到毛细胞的部位。虽然有强有力的证据表明，在噪声诱导的耳蜗损伤中，毛细胞变性的早期事件是膜破坏，但目前尚不清楚这种损伤是如何导致急性毛细胞死亡的。我们的长期目标是更好地了解噪音引起的听力损失的生物学和分子机制。本研究的目的是确定膜破坏在急性毛细胞死亡产生中的作用。本研究的中心假设是，膜功能障碍参与了急性毛细胞凋亡的调控。我们计划通过检查质膜的两个基本功能，膜屏障和膜粘附来检验我们的中心假设。具体地说,将解决以下三个目标:(1)确定膜透化作用的调控作用的急性头发细胞死亡和评价膜修复策略的影响在头发上细胞的机械应力,(2)确定的影响破坏膜粘附在毛细胞凋亡的细胞骨架结构,和(3)来识别apoptosis-related分子参与急性耳蜗损害的一代。我们在这里的贡献有望增加对急性毛细胞凋亡的调控机制的理解。这一贡献意义重大，因为对急性膜功能障碍的新见解填补了直接机械应力和随后导致细胞死亡的信号转导之间的知识空白。重要的是，控制细胞凋亡的膜事件可能导致抑制急性毛细胞死亡的新药理学策略的发展。

DESCRIPTION (provided by applicant): 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.