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New insights into the molecular regulation of mechanotransduction

力转导分子调控的新见解

基本信息

批准号：
10472251
负责人：
Lindsay Case
金额：
$ 143.1万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2022-09-15 至 2025-08-31
项目状态：
未结题

项目摘要

Project summary Cells exist in a physical world, and there is often a physical basis for human function and disease. Mechanotransduction is the molecular process by which cells sense and respond to mechanical signals in their environment. Abnormal mechanotransduction can contribute to many human diseases including asthma, heart failure, osteoporosis, and cancer. Thus, it is crucial to understand the molecular basis of mechanotransduction and how these signaling pathways are disrupted during disease. Integrin receptors are critical regulators of mechanotransduction at the plasma membrane that signal through the assembly supramolecular complexes termed “focal adhesions.” Focal adhesions physically connect the actin cytoskeleton to the extracellular environment, and forces generated in the actin cytoskeleton are transmitted across focal adhesions to drive tissue morphogenesis, cell movement, and extracellular matrix remodeling. Although the proper regulation of focal adhesions is essential for integrin-dependent mechanotransduction, important questions about their formation and function remain unanswered. We do not understand how focal adhesions form, how they grow, or how their molecular composition is regulated. Cell-based experiments have led to conflicting observations, and we have limited tools to understand how changing molecular composition can create focal adhesions with specific chemical or physical characteristics that alter downstream signaling. To address these important questions, Dr. Case has developed a novel biochemical reconstitution of focal adhesions using purified proteins on supported lipid bilayers. This work identified seven proteins that are sufficient to form focal adhesions through liquid-liquid phase separation. Studying integrin-dependent mechanotransduction through the lens of phase separation could drive significant advances in the field. The Case Lab will use a variety of experimental strategies to understand different aspects of integrin-dependent mechanotransduction. They will directly test different models of mechanotransduction with biochemical reconstitution and confirm the importance of any new in vitro observations with cell-based assays. They will investigate how focal adhesions mature, how forces are transmitted across focal adhesions, and how the biochemical composition of focal adhesions is regulated. This project will take advantage of a novel experimental approach to challenge the current dogma about integrin-dependent mechanotransduction, and will reveal how specific molecules regulate focal adhesion growth and composition.

项目摘要细胞存在于一个物理世界中，人类的功能和疾病往往有一个物理基础。机械转导是细胞在其生理过程中感知机械信号并对其作出反应的分子过程。环境异常的机械传导可以导致许多人类疾病，包括哮喘，心脏病，失败骨质疏松症和癌症因此，理解机械力传导的分子基础是至关重要的以及这些信号通路在疾病期间是如何被破坏的。整联蛋白受体是细胞凋亡的关键调节因子，通过组装超分子复合物在质膜上进行机械转导称为“局部粘连”局灶性粘连将肌动蛋白细胞骨架与细胞外基质连接起来，环境，肌动蛋白细胞骨架中产生的力通过粘着斑传递，组织形态发生、细胞运动和细胞外基质重塑。虽然适当的监管局灶性粘连对于整合素依赖性机械传导是必不可少的，关于其重要问题是，形成和功能仍然没有答案。我们不知道局灶性粘连是如何形成的，它们是如何生长的，它们的分子组成是如何被调节的基于细胞的实验导致了相互矛盾的观察结果，我们的工具有限，无法了解分子组成的变化如何导致局部粘连，改变下游信号传导的特定化学或物理特性。为了解决这些重要的问题，凯斯博士开发了一种新的生化重建方法，使用纯化的蛋白质在支持的脂质双层上进行局灶性粘连。这项工作确定了七种蛋白质，足以通过液-液相分离形成局部粘连。研究整合素依赖性通过相分离的透镜的机械转导可以推动该领域的重大进展。的案例实验室将使用各种实验策略来了解整合素依赖性机械传导他们将直接测试不同模型的机械转导与生化重组，并确认任何新的体外观察与基于细胞的测定的重要性。他们将研究局灶性粘连如何成熟，力如何通过局灶性粘连传递，以及局灶性粘连的生物化学组成受到调节。该项目将利用一种新颖的实验性的方法来挑战目前的教条整合素依赖的机械转导，并将揭示如何特定的分子调节粘着斑的生长和组成。