Regulation of cell adherence and motility is critical to the normal roles of many cells, but is also crucial to the development of pathologic conditions. Many of the components of the development and treatment of atherosclerosis rely on integrin and actin function. The importance of monocyte adherence and migration early in the development of atherosclerotic lesions and later migration of smooth muscle cells emphasize this point. The consequences of atherosclerotic disease are usually the result of acute thrombosis, requiring platelet adherence and activation. Therapy for atherosclerotic disease has many facets. An important aspect of current therapy is blockade of platelet adherence and activation. Future therapy may well be able to take advantage of drugs to specifically interfere with early events in the development of atherosclerosis. The adherence and migration of monocytes and smooth muscle cells are desirable targets. New therapy, which is being explored as a part of this SCOR, is neovascularization to circumvent the compromised blood supply in patients with coronary artery disease. It is evident from angiogenesis studies in tumors that integrin function regulates vessel growth. We propose to study the basic mechanisms that lead to activation of integrins and adherence and regulation of actin polymerization, the driving force of migrating cells. We have developed a permeabilized platelet system which has allowed us to define the signaling pathways and molecules that lead to GPIIb/IIIa activation and actin uncapping in response to thrombin. We propose to extend these studies to determine the pathways used by other platelet agonists to activate GPIIb/IIIa. We will then more fully define the pathway used by thrombin and other agonists to activate GPIIb/IIIa. We have found that thrombin mediates actin uncapping in platelets by stimulating PtdIns-4,5-P2 synthesis. We will further define this pathway and investigate the pathways used by other platelet agonists. We will then apply this knowledge to study the activation of integrins in monocytes, smooth muscle cells and endothelial cells. We will also investigate the signals leading to actin uncapping in these cells, a prerequisite to migration. The results of these studies will broaden our knowledge of the basic cellular mechanisms leading to atherosclerosis and provide a stepping-stone to better therapies.
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