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: 8360182
• 负责人: ROBERT A HARRIS
• 金额: $ 17.15万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360182
• 关键词: Actins; Acute; Atherosclerosis; Biology; Biomedical Research; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular Pathology; Cell physiology; Cells; Cellular Structures; Chemicals; Complex; Contracts; Cues; Cytoskeletal Modeling; Development; Down-Regulation; Economics; Environment; Event; Fluorescence Microscopy; Funding; Goals; Grant; Growth; Growth Factor; Heart; Human; Hypertension; Hypertrophy; Knowledge; Light; Liquid substance; Mechanical Stress; Mechanics; Mediating; Molecular; Morbidity - disease rate; Muscle Contraction; National Center for Research Resources; Nature; Pathology; Pathway interactions; Principal Investigator; Research; Research Infrastructure; Research Project Grants; Resources; Resveratrol; Role; Signal Transduction; Signaling Molecule; Signaling Protein; Smooth Muscle; Smooth Muscle Myocytes; Source; Stimulus; Stretching; Structure; Techniques; Therapeutic Agents; Uncertainty; United States National Institutes of Health; Vascular System; West Virginia; cost; cytokine; design; interest; migration; mortality; receptor; response; restenosis; shear stress; solid state

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A fundamental problem in biology is to understand how cells are able to sense and respond to environment cues. The integration of chemical signals such as growth factors and cytokines with mechanical stimuli is not well understood. The place where cascades involved in solid-state (mechanical) signaling and soluble (chemical) signaling converge and the manner in which they interact is no doubt complex. This research project is designed to investigate signaling events associated with both chemical and mechanical stimuli. Cells of the vascular 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, including enhanced growth and migration, seem to be important in the pathological conditions that accompany cardiovascular diseases such as atherosclerosis, hypertension, and restenosis. Cardiovascular disease remains a major cause of morbidity and mortality in the U.S. and the economic and human costs associated with these pathologies are enormous. This has resulted in an intense research interest in the mechanisms which regulate contraction, migration, and growth of vascular smooth muscle cells (VSMC). While it is now clear that mechanical forces imposed on cells of the vessel wall are important factors in the initiation and progression of pathological 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 overall goal of this project is to elucidate the acute responses in cytoskeletal reorganization that occur during mechanical stress of VSMC and to determine the intracellular signaling mechanisms that are involved. 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. Further, we will make a systematic determination of the effects of various types of mechanical stress on activation of cell signaling molecules. In addition, we will 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 down-regulate 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 down-regulation 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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 生物学的一个基本问题是了解细胞如何能够感知和对环境线索的反应。 尚不清楚化学信号（例如生长因子和细胞因子与机械刺激）的整合。 级联参与固态（机械）信号传导和可溶（化学）信号转导的地方，它们相互作用的方式无疑是复杂的。 该研究项目旨在研究与化学和机械刺激相关的信号事件。 血管系统的细胞不断暴露于机械力的作用，例如拉伸和流体剪切应力。 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，包括增强和迁移，似乎在伴随心血管疾病（例如动脉粥样硬化，高血压和再狭窄）的病理状况中很重要。在美国，心血管疾病仍然是发病率和死亡率的主要原因，与这些病理相关的经济和人为成本是巨大的。 这引起了对调节血管平滑肌细胞（VSMC）的收缩，迁移和生长的机制的强烈研究兴趣。 虽然现在很明显，施加在血管壁细胞上的机械力是病理变化的启动和进展的重要因素，但这些适应中涉及的分子机制尚未完全了解。 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。该项目的总体目标是阐明在VSMC机械应力期间发生的细胞骨架重组中的急性反应，并确定所涉及的细胞内信号传导机制。 利用分子方法与荧光显微镜结合，并依赖细胞取向和肌动蛋白细胞骨架重组的精确变化，作为定量评估机械应变响应性的终点，我们将评估各种细胞骨架结构对VSMC对伸展的响应的各种细胞骨架结构的作用。 此外，我们将系统地确定各种类型的机械应力对细胞信号分子激活的影响。 此外，我们将评估白藜芦醇（一种声称的心脏保护分子）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转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。