Mechanisms of Mechanotransduction by LIM Domain Proteins

项目摘要 LIM结构域蛋白的机械转导机制 机械力是控制形状、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的缺陷 机械反应与包括动脉粥样硬化在内的多种疾病有关， 心力衰竭和癌症。一个主要的挑战是理解机械转导-- 机械信息被检测和传递到的机制 控制细胞行为的途径。LIM超级蛋白质家族，其中包含一种 或更多的LIM结构域，代表大量可能的机械敏感细胞 参与生理机械转导途径的蛋白质。 了解LIM域如何工作以检测和传输有关信息 机械应力将导致对机械传递基础的更深层次的理解 信号，这对于制定疾病治疗和器官的策略是重要的 再生。 这一提议利用了细胞生物物理学、生物化学 分子细胞生物学、活细胞成像和数学模型来研究 肌动蛋白细胞骨架中LIM结构域感知机械刺激的机制 进而启动YAP/TAZ机械转导信号转导。我们最近发现 大量的LIM结构域显示出与肌动蛋白细丝的力敏感结合。这里 我们建议：(1)确定LIM蛋白被招募到 机械应力肌动蛋白细丝，(2)确定LIM序列如何使 肌动蛋白细胞骨架内力依赖的募集的特异性和(3)阐明 LIM蛋白LIMD1的机械传感如何启动YAP/TAZ 机械转导途径。这些研究有可能证明高度的 细胞机械传感的保守机制，并将建立一种 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.