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

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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.