MECHANOTRANSDUCTION, INTRACELLULAR SIGNALING AND VASCULAR BIOLOGY

机械传导、细胞内信号传导和血管生物学

• 批准号: 8167674
• 负责人: ROBERT A HARRIS
• 金额: $ 18.52万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167674
• 关键词: Actins; Acute; Atherosclerosis; Biology; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cells; Cellular Structures; Computer Retrieval of Information on Scientific Projects Database; Contracts; Cytoskeletal Modeling; Development; Down-Regulation; Economics; Fluorescence Microscopy; Funding; Goals; Grant; Growth; Heart; Human; Hypertension; Hypertrophy; Institution; Knowledge; Light; Liquid substance; Mechanical Stress; Mechanics; Mediating; Molecular; Morbidity - disease rate; Muscle Contraction; Nature; Pathology; Pathway interactions; Research; Research Personnel; Resources; Resveratrol; Role; Signal Transduction; Signaling Molecule; Signaling Protein; Smooth Muscle; Smooth Muscle Myocytes; Source; Stretching; Structure; Techniques; Therapeutic Agents; United States National Institutes of Health; cost; interest; migration; mortality; receptor; response; restenosis; shear stress

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cells of the cardiovascular system are continuously exposed to the effects of mechanical forces such as stretching and fluid shear stress. These forces, which are created by the pulsatile nature of blood flow when the heart contracts and relaxes, have a marked influence on cell structure and function. The adaptations of these cells, which include enhanced growth and migration, seem to be important in the pathological conditions that accompany cardiovascular diseases such as atherosclerosis and hypertension. Cardiovascular disease remains a major cause of morbidity and mortality in the US and the economic and human costs associated with pathologies such as atherosclerosis, hypertension and restenosis are enormous. This has resulted in an intense research interest in the mechanisms which regulate contraction, migraton and growth of vascular smooth muscle cell (VSMC). While it is now clear that mechanical forces imposed on VSMC in the vessel wall are important factors in the initiation and progression of these changes, the molecular mechanisms involved in these adaptations are not fully understood. In addition, it is now clear that the basic mechanism of smooth muscle contraction can only be explained in light of actin remodeling. However, the exact nature of cytoskeletal reorganization and the mechanisms regulating these changes are not well known. The main goal of this project to is to elucidate the acute response in cytoskeletal reorganization and intracellular signaling and during mechanical stress of VSMC. Utilizing molecular approaches combined with fluorescence microscopy, and relying on the precise changes in cell orientation and actin cytoskeletal reorganization as endpoints for quantitative assessment of responsiveness to mechanical strain we will evaluate the role of various cytoskeletal structures on the response of VSMC to stretch, make a systematic determination of effects of various types of mechanical stress on activation of cell signaling molecules, and evaluate the effects of resveratrol, a purported cardioprotective molecule for its potential effects on stretch-induced cell signaling and receptor mediated cellular hypertrophy. The use of pharmacologic and molecular techniques to stabilize, destabilize or downregulate specific cytoskeletal components is expected to provide clear answers concerning the role of specific components in mechanotransduction and the cell orientation response. The inhibition or downregulation of specific signaling proteins is expected to provide information concerning pathways regulating mechanosensing and transduction. The knowledge gained may be useful in the development of therapeutic agents regulating mechanotransduction mechanisms contributing to cardiovascular pathologies.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 心血管系统的细胞不断暴露于诸如拉伸和流体剪切应力之类的机械力的影响。 这些力是由于心脏收缩和放松时血流的脉动性质所产生的，对细胞结构和功能产生了明显影响。 这些细胞的适应包括增强的生长和迁移，在伴随心血管疾病（如动脉粥样硬化和高血压）的病理状况中似乎很重要。心血管疾病仍然是美国发病率和死亡率的主要原因，以及与动脉粥样硬化，高血压和再狭窄等病理相关的经济和人为成本。 这引起了对调节收缩，迁移和血管平滑肌细胞（VSMC）生长的机制的强烈研究兴趣。 虽然现在很明显，在容器壁中施加的VSMC的机械力是这些变化的启动和进展的重要因素，但尚未完全了解这些适应性的分子机制。 此外，现在很明显，平滑肌收缩的基本机制只能根据肌动蛋白的重塑来解释。 但是，尚不清楚细胞骨架重组的确切性质和调节这些变化的机制。该项目的主要目标是阐明细胞骨架重组和细胞内信号传导以及VSMC机械应力期间的急性反应。 利用分子方法与荧光显微镜相结合，并依靠细胞取向和肌动蛋白细胞骨骼重组的精确变化作为终点，以定量评估对机械应变的响应性的定量评估，我们将评估各种细胞骨架结构对VSMC响应的各种细胞对延伸的响应的作用，使其对延伸的反应进行效应的机制效应，使其具有系统的效果，使其具有系统的效果。白藜芦醇是一种据称的心脏保护分子的影响，其对拉伸诱导的细胞信号传导和受体介导的细胞肥大的潜在影响。 预计使用药理学和分子技术来稳定，不稳定或下调特定的细胞骨架成分，可以提供有关特定成分在机械传导和细胞方向反应中的作用的明确答案。 预计特定信号蛋白的抑制或下调有望提供有关调节机械传感和转导的途径的信息。 获得的知识可能对调节导致心血管病理的机械转导机制的治疗剂的发展有用。