Noise-induced acute hair cell Death

描述（由申请人提供）：细胞质膜在维持细胞稳态中起重要作用。它也是将机械力传递到毛细胞的第一个部位。虽然强有力的证据表明，膜破坏是噪声诱导的耳蜗创伤中毛细胞变性的早期事件，但尚不清楚这种损伤如何导致急性毛细胞死亡的发病机制。我们的长期目标是更好地了解噪声性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中的作用。这项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节。我们计划通过检查质膜的两个基本功能，膜屏障和膜粘附来测试我们的中心假设。具体而言，将实现以下三个目标：（1）确定膜透化在急性毛细胞死亡的调节中的作用，并评估膜修复策略对毛细胞对机械应力的响应的影响，（2）确定膜粘附的破坏对凋亡毛细胞的细胞骨架结构的影响，以及（3）鉴定参与急性耳蜗损伤的产生的耳蜗损伤相关分子。我们的贡献有望增加对急性毛细胞凋亡调控机制的理解。这一贡献是重要的，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的药理学策略的发展。

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.