Molecular basis understanding of recruitment of monocytes into atherosclerotic lesions under physiological flow

生理流下单核细胞募集至动脉粥样硬化病变的分子基础理解

• 批准号: 345322-2007
• 负责人: Yang, Jun
• 金额: $ 2.97万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Research Tools and Instruments - Category 1 (<$150,000)
• 财政年份: 2006
• 资助国家: 加拿大
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=326291
• 关键词: Molecular; basis; understanding; recruitment; monocytes

Atherosclerosis is an inflammatory disease of the vessel wall, where fatty materials, cholesterol and cellular waste products accumulate. At all stages of development of atherosclerosis, monocytes are recruited to atherosclerotic lesions. Recruitment of monocytes to sites of atherosclerotic lesions is a multistep process, including cell tethering, rolling, firm adhesion on endothelial cells and transmigration across vascular walls. This multi-step cascade is mediated the coupling effects of both cell adhesion molecules interactions and hydrodynamic forces of physiological flow. And hence, bound cell adhesion molecules are mechanically stressed. Interactions between alpha4beta1 integrin and its ligands, vascular adhesion molecule-1 (VCAM-1) and fibronectin (Fn), play a key role in the recruitment of monocytes into atherosclerotic lesions. These interactions have not been well determined, especially under force application. In this project, we propose to quantitatively define the kinetics and mechanics of alpha4beta1-VCAM-1 and alpha4beta1-Fn interactions using AFM (Atomic Force Microscopy).       AFM is a robust tool that is suitable for detecting molecular force in liquid environment. In this proposal, funds are requested for an economical AFM, which includes basic control software and modules for force measurement.       This study will generate detailed biophysical data for interactions of alpha4beta1 integrin with their ligands. These data will advance our understanding of monocyte infiltration into atherosclerotic lesions, and may provide insights to drug discovery and therapeutics of cardiovascular diseases, which are our long-term goals.

动脉粥样硬化是血管壁的炎性疾病，其中脂肪物质、胆固醇和细胞废物积聚。在动脉粥样硬化发展的所有阶段，单核细胞被募集到动脉粥样硬化病变。单核细胞向动脉粥样硬化病变部位的募集是一个多步骤的过程，包括细胞束缚、滚动、在内皮细胞上牢固粘附和穿过血管壁的迁移。这种多步骤级联介导的细胞粘附分子相互作用和生理流动的流体动力学的耦合效应。因此，结合的细胞粘附分子受到机械应力。α 4 β 1整合素与其配体血管粘附分子-1（VCAM-1）和纤连蛋白（Fn）之间的相互作用在单核细胞募集到动脉粥样硬化病变中起关键作用。这些相互作用还没有很好地确定，特别是在力的应用。在这个项目中，我们建议使用AFM（原子力显微镜）定量定义α 4 β 1-VCAM-1和α 4 β 1-Fn相互作用的动力学和力学。 原子力显微镜（AFM）是一种适用于液体环境中分子力检测的强大工具。在这一提案中，要求提供资金用于经济型AFM，其中包括基本控制软件和测力模块。 本研究将产生α 4 β 1整合素与其配体相互作用的详细生物物理数据。这些数据将促进我们对单核细胞浸润到动脉粥样硬化病变的理解，并可能为心血管疾病的药物发现和治疗提供见解，这是我们的长期目标。