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物理世界中，并且通常存在人类功能和疾病的物理基础。机械转导是分子过程，细胞在其中感知并响应其机械信号环境。异常机械转传会导致许多人类疾病，包括哮喘，心脏失败，骨质疏松和癌症。这一点至关重要的是要了解机械转导的分子基础以及这些信号通路如何破坏疾病。整联蛋白受体是关键的调节剂质膜上的机械转导，该质膜通过装配超分子复合物发出信号称为“焦点粘合剂”。焦点粘合剂实际将肌动蛋白细胞骨架与细胞外连接环境和肌动蛋白细胞骨架中产生的力跨焦点粘合剂传播以驱动组织形态发生，细胞运动和细胞外基质重塑。虽然适当的法规焦点广告对于依赖整联蛋白的机械传输至关重要，有关其的重要问题形成和功能仍未得到解答。我们不了解焦点广告的形式，它们的成长方式或如何调节它们的分子组成。基于细胞的实验导致了相互冲突的观察结果，并且我们有有限的工具来了解变化的分子组成如何与特定的化学或物理特性改变了下游信号传导。为了解决这些重要问题，凯斯博士开发了一种新颖的生化重构使用纯化的蛋白质在受支持的脂质双层的焦点广告。这项工作确定了七个蛋白质足以通过液态液相分离形成焦点粘合剂。研究整联蛋白依赖性通过相位分离镜头的机械转导可能会带来该田间的重大进展。这案例实验室将使用各种实验策略来了解整合素的不同方面机械转导。他们将直接通过生化测试不同的机械转移模型重建并确认对基于细胞测定的任何新体外观察的重要性。他们会的研究焦点粘合剂如何成熟，如何在焦点粘合剂之间传播力以及如何调节焦点粘合剂的生化组成。该项目将利用一个新颖的实验挑战当前关于整联蛋白依赖性机械转导的教条的方法，并将揭示如何特定的分子调节局灶性粘合剂的生长和组成。