Mechanisms of Mechanotransduction by LIM Domain Proteins

项目摘要 LIM结构域蛋白的力学信号转导机制 机械力对于控制形状、运动甚至许多 细胞生理学的各个方面。环境力学的变化或细胞缺陷 机械反应与包括动脉粥样硬化在内的多种疾病有关， 心脏衰竭和癌症一个主要的挑战是理解机械转导- 机械信息被检测并传送到 控制细胞行为的途径。LIM蛋白质超家族，其中包含一个 或多个LIM结构域，代表了大量推定的机械敏感性细胞 参与生理机械传导途径的蛋白质。 了解LIM域如何运行以检测和传输有关 机械应力将导致更深入地了解机械转导为基础的 信号传导，这对于制定疾病治疗和器官移植的策略非常重要。 再生 这项提议利用了细胞生物物理学、生物化学 分子细胞生物学，活细胞成像和数学建模来研究 LIM结构域在肌动蛋白细胞骨架中感知机械刺激的机制 并依次启动雅普/TAZ机械转导信号。我们最近发现 大量的LIM结构域表现出与肌动蛋白丝的力敏结合。这里 我们建议：（1）确定LIM蛋白被招募的机制， 机械应力肌动蛋白丝，（2）确定LIM序列如何使 在肌动蛋白细胞骨架内的力依赖性募集的特异性和（3）阐明 LIM蛋白LIMD 1的机械传感如何启动雅普/TAZ 机械传导途径这些研究有可能证明， 保守的机制，细胞机械传感，和方法将建立一个 解决细胞机械转导的新策略。

Project Summary Mechanisms of Mechanotransduction by LIM Domain Proteins Mechanical forces are essential to controlling the shape, movement and even many aspects of cell physiology. Changes in the environment mechanics or defects in cellular mechanoresponse are implicated in a plethora of diseases including atherosclerosis, heart failure and cancer. A major challenge is to understand mechanotransduction - the mechanisms by which mechanical information is detected and communicated to pathways that control cell behavior. The LIM super family of proteins, which contain one or more LIM domains, represents a large number of putative mechanosensitive cellular proteins that are involved in physiological mechanotransduction pathways. Understanding how the LIM domains function to detect and transmit information about mechanical stress will result in a deeper understanding of mechanotransduction-based signaling, which is important for developing strategies of disease treatment and organ regeneration. This proposal leverages an innovative combination of cell biophysics, biochemistry molecular cell biology, live cell imaging and mathematical modeling to investigate the mechanism by which LIM domains sense mechanical stimuli in the actin cytoskeleton and, in turn, initiate YAP/TAZ mechanotransduction signaling. We recently discovered that a large number of LIM domains exhibit force-sensitive binding to actin filaments. Here we propose to: (1) identify the mechanism by which LIM proteins are recruited to mechanically stressed actin filaments, (2) determine how the LIM sequence enables specificity in force-dependent recruitment within the actin cytoskeleton and (3) elucidate how the mechanosensing by LIM protein LIMD1 initiates the YAP/TAZ mechanotransduction pathway. These studies have the potential to demonstrate a highly conserved mechanism of cell mechanosensing, and the methodologies will establish a novel strategy for tackling cell mechanotransduction.