Ultrastructural Basis of Mechanotransduction in Matrix Adhesions

描述（由申请人提供）：本项目的总体目标是详细了解整合素介导的粘附如何成熟以及该过程如何决定信号输出。黏附成熟高度依赖于物理力量，无论是来自内源性肌球蛋白还是通过细胞外基质施加的外力。因此，比较正常粘附的超微结构和动力学与施加力的反应将阐明机械转导的机制。本项目将开发基质粘附的机械转导模型，该模型集成了粘附的超微结构、生化相互作用、多蛋白组装和信号网络的时空动力学。我们将在细胞迁移的背景下分析机械转导作为粘附力学和信号传导的重要生理输出。为了实现这一目标，我们组建了一个长期合作的独特团队，他们将实施多方面的实验方法，包括分子细胞生物学，生物化学，生物物理方法，材料科学，计算和数学分析，以及相关的高分辨率光学和电子显微镜。

DESCRIPTION (provided by applicant): The overall goal of this Program Project is to understand in detail how integrin-mediated adhesions mature and how this process determines signaling outputs. Adhesion maturation is highly dependent on physical forces, whether from endogenous myosin or applied externally through the extracellular matrix. Thus, comparison of normal adhesion ultrastructure and dynamics with responses to applied force will elucidate mechanisms of mechanotransduction. This Program Project will develop a model for mechanotransduction at matrix adhesions that integrates adhesion ultrastructure, biochemical interactions, temporal and spatial dynamics of multiprotein assemblies and signaling networks. We will analyze mechanotransduction in the context of cell migration as an important physiological output of adhesion mechanics and signaling. To achieve this, we have formed a unique team of long-standing collaborators who will implement a multifaceted experimental approach that includes molecular cell biology, biochemistry, biophysical approaches, material science, computational and mathematical analysis, and correlated high-resolution light and electron microscopy.