Cardiomyocyte mechanotransduction through the integrin complex

描述（由申请人提供）：机械转导是细胞感知外力并以生物活性响应的过程。在心肌中，心肌细胞被认为通过细胞膜上的整合素复合物感知和传递细胞内外的力。本研究将探讨细胞骨架中膜整合素和整合素相关结构蛋白在力传递中的作用。当这些机械途径被破坏时，心脏扩张、舒张功能障碍和心力衰竭就会发生。整合素复合物的缺陷导致心室功能障碍的主要途径有两种：第一，细胞外基质与内部细胞骨架之间的直接机械联系可能存在缺陷，导致力传递改变，从而导致舒张功能障碍；第二，由外而内的机械感知缺陷将改变肌细胞的肥厚和重塑反应。我们将使用整合素和整合素相关蛋白（vinculin和PINCH）缺陷的小鼠模型来研究整合素复合物的意义，整合素和整合素相关蛋白被认为是细胞膜应力传感和力传递的关键成分。将要测试的假设是：(1)左心室的弹性反冲和舒张舒张是通过整合素复合体的机械连接直接调节的；(2)通过整合素复合物的力传递和机械转导是方向依赖的；(3)整合素蛋白胞内组分的功能决定了其机械转导特性。为了验证这些假设，心肌细胞和组织使用了最先进的实验技术，包括磁共振成像、原子力显微镜和分离组织测试，以及基于细胞的功能分析。通过了解与机械转导相关的蛋白质的功能，我们将推进我们对心肌肥厚、心肌病、向心力衰竭过渡以及重要的心肌舒张功能的发病机制的认识。

DESCRIPTION (provided by applicant): Mechanotransduction is the process by which cells sense external forces and respond with biological activity. In the myocardium, the cardiac myocytes are thought to sense and transmit forces both in and out of the cell through the integrin complex at the cellular membrane. This research will investigate the role of the membrane integrins and integrin-associated structural proteins within the cytoskeleton in force transmission. When these mechanical pathways are disrupted, cardiac dilation, diastolic dysfunction and heart failure can occur. There are there are two main pathways by which defects in the integrin complex results in dysfunction of the ventricle: first, the direct mechanical linkage between the extracellular matrix and the internal cytoskeleton can be defective, resulting in altered force transmission and hence diastolic dysfunction, and second, a defect in mechanosensing, from the outside in, will alter the hypertrophic and remodeling responses of the myocytes. We will investigate the significance of the integrin complex using mouse models with defective integrin and integrin-related proteins (vinculin and PINCH), which are thought to be critical components of stress sensing and force transmission at the cell membrane. The hypotheses that will be tested are (1) elastic recoil and diastolic relaxation of the left ventricle are modulated directly through mechanical linkages at the integrin complex; (2) Force transmission and mechanotransduction through the integrin complex are direction-dependent; (3) Function of the intracellular components of the integrin protein determines its mechanotransduction properties. To test these hypotheses, myocardial cells and tissues are used with state of the art experimental techniques, including magnetic resonance imaging, atomic force microscopy and isolated tissue testing, as well as cell- based functional assays. By understanding function of the proteins linked to mechanotransduction, we will advance our knowledge of the pathogenesis of cardiac hypertrophy, cardiomyopathy, the transition to heart failure and importantly, diastolic function of the myocardium. PUBLIC HEALTH RELEVANCE: This research examines the significance of forces transmitted into and out of cardiac myocytes, which play a significant role in remodeling responses of the heart tissue to overloads such as hypertension. Mouse models with defects in proteins responsible for mechanical force transmission will enable us to determine their role and how they can possibly be modified to prevent abnormal cellular and tissue responses leading the cardiac dilation and heart failure.