Mechanisms of Mechanotransduction by LIM Domain Proteins

LIM 结构域蛋白的力转导机制

基本信息

批准号：
10522418
负责人：
Margaret Lise Gardel
金额：
$ 40.88万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522418
关键词：
Actins Adherens Junction Affect Affinity Apoptosis Atherosclerosis Avidity Binding Biochemistry Biophysics Cell Proliferation Cell Size Cell physiology Cells Cellular Metabolic Process Cellular Stress Cellular biology Collaborations Comparative Study Cues Cytoskeleton Defect Development Disease Elements Environment Epithelial Epithelial Cells Exhibits Family Focal Adhesions Heart failure Hydrophobicity In Vitro Investigation Knowledge LIM Domain LIM Domain Protein Malignant Neoplasms Mammalian Cell Measures Mechanical Stress Mechanics Methodology Microfilaments Modeling Modernization Molecular Molecular Conformation Monitor Movement Organelles Pathway interactions Periodicity Phenylalanine Physiological Physiology Process Protein Family Proteins Regulation Series Shapes Signal Pathway Signal Transduction Sorting - Cell Movement Specificity Stress Stress Fibers Surface Testing Tissues ZYX gene base cell behavior experimental study innovation insight live cell imaging mathematical model mechanical force mechanical signal mechanical stimulus mechanotransduction multi-scale modeling multidisciplinary novel strategies organ regeneration paxillin reconstitution recruit

项目摘要

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.

项目概要 LIM 结构域蛋白的力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的缺陷机械反应与多种疾病有关，包括动脉粥样硬化、心力衰竭和癌症。一个主要的挑战是理解机械转导—— 检测机械信息并将其传达给的机制控制细胞行为的途径。 LIM 蛋白质超家族，其中含有一种或更多 LIM 结构域，代表大量推定的机械敏感细胞参与生理机械传导途径的蛋白质。了解 LIM 域如何检测和传输相关信息机械应力将导致对基于机械传导的更深入的理解信号传导，这对于制定疾病治疗和器官策略非常重要再生。该提案利用了细胞生物物理学、生物化学的创新组合分子细胞生物学、活细胞成像和数学建模来研究 LIM 结构域感知肌动蛋白细胞骨架中的机械刺激的机制并依次启动 YAP/TAZ 机械转导信号传导。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感结合。这里我们建议：（1）确定 LIM 蛋白被招募到的机制机械应力肌动蛋白丝，(2) 确定 LIM 序列如何实现肌动蛋白细胞骨架内力依赖性募集的特异性，以及（3）阐明 LIM 蛋白 LIMD1 的机械传感如何启动 YAP/TAZ 力传导途径。这些研究有可能证明高度细胞机械传感的保守机制，该方法将建立一个解决细胞力转导的新策略。