Ultrastructural Basis of Mechanotransduction in Matrix Adhesions

基质粘附力传导的超微结构基础

• 批准号: 8165563
• 负责人: DORIT HANEIN
• 金额: $ 157.34万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165563
• 关键词: Ultrastructural; Basis; Mechanotransduction; Matrix; Adhesions

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.

描述（由申请人提供）：该计划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。粘附成熟高度依赖于物理力，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部力。因此，正常粘附超微结构和动力学与对施加力的响应的比较将阐明机械转导的机制。该计划项目将开发一种基质粘附力机械转导模型，该模型集成了粘附超微结构、生化相互作用、多蛋白组装的时间和空间动力学以及信号网络。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，我们组建了一个由长期合作者组成的独特团队，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。 公共健康相关性：基质粘附感知其机械环境，从而调节调节增殖、分化、迁移和细胞死亡的信号。因此，力量的变化会产生发育缺陷，并导致血管和慢性炎症疾病、肿瘤形成和转移。 尽管其重要性，但将力转变成生物信号的机制尚不清楚。我们的多方面方法将揭示其机制和结构基础。