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连是如何成熟的，以及这一过程如何确定信号输出。黏附的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于外部。因此，将正常黏附的超微结构和动力学与对外力的反应进行比较，将有助于阐明机械转导的机制。该计划项目将开发一个在基质粘连处进行机械转导的模型，该模型集成了粘连超微结构、生化相互作用、多蛋白组装和信号网络的时间和空间动力学。我们将在细胞迁移的背景下分析机械转导，作为黏附机制和信号转导的重要生理产物。为了实现这一目标，我们组建了一个由长期合作伙伴组成的独特团队，他们将实施一种多方面的实验方法，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。 与公共健康相关：基质粘连感知其机械环境，从而调节调节增殖、分化、迁移和细胞死亡的信号。因此，力量的转移可能会产生发育缺陷，并导致血管和慢性炎症性疾病、肿瘤形成和转移。尽管它很重要，但力转化为生物信号的潜在机制尚不清楚。我们的多方面方法将揭示其机制和结构基础。

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. PUBLIC HEALTH RELEVANCE: Matrix adhesions sense their mechanical environment and thereby modulate signals that regulate proliferation, differentiation, migration, and cell death. Shifts in force, therefore, can produce developmental defects and contribute to vascular and chronic inflammatory diseases, tumor formation and metastasis. Despite its importance, the mechanism underlying the transduction of force to biological signal is not understood. Our multifaceted approach will reveal its mechanistic and structural basis.