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

动脉粥样硬化是一种血管壁炎性疾病，脂肪物质、胆固醇和细胞废物积聚在血管壁上。在动脉粥样硬化发展的所有阶段，单核细胞都被招募到动脉粥样硬化病变中。单核细胞在动脉粥样硬化病变部位的募集是一个多步骤的过程，包括细胞捆绑、滚动、与内皮细胞的牢固黏附和跨血管壁迁移。这种多步骤级联反应是细胞黏附分子相互作用和生理流水动力共同作用的结果。因此，结合的细胞黏附分子受到机械压力。α4beta1整合素与其配体血管黏附分子-1(VCAM-1)和纤维连接蛋白(FN)之间的相互作用在单核细胞向动脉粥样硬化病变的募集中起着关键作用。这些相互作用还没有很好地确定，特别是在施力的情况下。在这个项目中，我们建议使用原子力显微镜(AFM)来定量定义α4beta1-VCAM-1和α4beta1-FN相互作用的动力学和力学。研究表明，AFM是一种强大的工具，适用于检测液体环境中的分子力。在这项提案中，需要为经济型原子力显微镜提供资金，其中包括基本的控制软件和测力模块。他说，这项研究将为alpha4beta1整合素与其配体的相互作用生成详细的生物物理数据。这些数据将促进我们对单核细胞渗入动脉粥样硬化病变的理解，并可能为我们的长期目标--心血管疾病的药物发现和治疗提供见解。

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.