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.

项目摘要 LIM结构域蛋白质转导的机理机械力对于控制形状，运动甚至许多细胞生理的各个方面。环境力学的变化或细胞中的缺陷机械响应与多种疾病有关，包括动脉粥样硬化，心力衰竭和癌症。一个主要的挑战是了解机械转移 - 检测机械信息并传达给机械信息的机制控制细胞行为的途径。 Lim超级蛋白质，其中包含一个或更多的LIM域，代表大量推定的机械敏感性细胞涉及生理机械转导途径的蛋白质。了解LIM域的功能如何检测和传输有关机械应力将导致对基于机械转传的更深入了解信号传导，这对于制定疾病治疗和器官的策略很重要再生。该建议利用细胞生物物理学，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，以研究 LIM域在肌动蛋白细胞骨架中感知机械刺激的机制然后，启动YAP/TAZ机械传导信号传导。我们最近发现大量的LIM结构域表现出对肌动蛋白丝的力敏感性结合。这里我们建议：（1）确定招募LIM蛋白的机制机械应力的肌动蛋白丝，（2）确定LIM序列如何启用在肌动蛋白细胞骨架内的力依赖性募集中的特异性和（3）阐明 LIM Protein LIMD1的机械感应如何启动YAP/TAZ 机械转导途径。这些研究有可能证明细胞机械感应的保守机制，方法学将建立解决细胞机械转导的新型策略。