Unraveling Integrin Mechanotransduction with Molecular Imaging

用分子成像揭示整合素机械转导

• 批准号: 9386933
• 负责人: Tristan P Driscoll
• 金额: $ 0.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386933
• 关键词: Actins; Adhesions; Affect; Arteries; Atherosclerosis; Behavior; Blood Pressure; CD31 Antigens; Cell Adhesion; Cell physiology; Cells; Cellular Structures; Cytoplasmic Tail; Disease; Endothelial Cells; Energy Transfer; Exercise; Extracellular Matrix; F-Actin; Fibroblasts; Filament; Fluorescence Resonance Energy Transfer; Focal Adhesions; Goals; Growth; Homeostasis; Hypertension; Image; Imagery; Integrin Binding; Integrins; Label; Malignant Neoplasms; Measurement; Measures; Mechanics; Mediating; Methods; Microfilaments; Microscopy; Molecular; Morphogenesis; Movement; Myosin ATPase; Osteogenesis; Osteoporosis; Output; Pattern; Physiology; Play; Polymers; Process; Proteins; Regulation; Resolution; Role; Signal Transduction; Silk; Spiders; Stretching; Structure; Surface; System; Talin; Thinking; Time; Tissues; Vascular Diseases; Vinculin; Weight-Bearing state; alpha Actinin; base; bone turnover; cadherin 5; fluid flow; human disease; imaging modality; insight; mechanical force; mechanotransduction; molecular dynamics; molecular imaging; new technology; polymerization; protein aminoacid sequence; public health relevance; response; sensor; single molecule; stem cell differentiation; stoichiometry; temporal measurement; tumor progression

 DESCRIPTION (provided by applicant): Mechanical forces are key regulators of cellular function for both normal growth and homeostasis of tissues, and in diseases including atherosclerosis, hypertension, osteoporosis and cancer. Understanding the mechanisms by which cells sense and respond to mechanical forces is therefore critical for understanding normal physiology and these disease states. Integrin-mediated adhesions provide the primary linkage through which cells both transmit and sense mechanical forces between the extracellular matrix (ECM) and the cytoskeletal networks within the cell. Current views of mechanosensing center on the concept of a "molecular clutch" that connects the immobile, bound integrins to rearward moving actin filaments. These connections are formed through load-bearing linker molecules such as talin. Thus, forces are sensed by an intrinsically dynamic assembly whose behavior is modified by mechanical forces. Understanding this system in molecular detail is the goal of the project. The Schwartz lab has developed molecular force sensors that allow spatial and temporal measurement of tension across specific proteins. I propose to combine a talin tension sensor with fluorescent speckle microscopy for visualization of actin filament assembly, movement and disassembly. This approach will allow simultaneous analysis at near-single molecule levels of the forces and dynamics within cell adhesions. This will be done while varying both cell-derived and externally applied forces. Determining how forces modulate the molecular dynamics within the adhesions will provide fundamental insights into the molecular mechanisms of mechanotransduction by integrin-mediated adhesions.

 描述（由适用提供）：机械力是组织正常生长和组织稳态的细胞功能的关键调节剂，以及包括动脉粥样硬化，高血压，骨质疏松和癌症在内的疾病。因此，了解细胞感知和对机械力反应的机制对于理解正常生理和这些疾病状态至关重要。整联蛋白介导的粘着提供了主要的联系，细胞在细胞外基质（ECM）和细胞内的细胞骨架网络之间均传递和感官机械力。机理的当前视图集中在“分子离合器”的概念上，该概念将固定的整合素连接到后向移动的肌动蛋白丝。这些连接是通过承重的接头分子（例如塔林）形成的。这是通过内在动态组装来感知力的，其行为是通过机械力改变的。分子细节了解该系统是该项目的目标。 Schwartz实验室开发了分子力传感器，可允许在特定蛋白质上对张力进行空间和临时测量。我建议将塔林张力传感器与荧光斑点显微镜相结合，以可视化肌动蛋白丝组装，运动和拆卸。这种方法将允许在细胞粘附内部力和动力学的近节分子水平上进行简单分析。这将在改变细胞衍生和外部施用力时进行。确定力如何调节粘合剂内的分子动力学将提供基本的见解，以对整合素介导的广告进行机理的分子机制。