Genetic and Cellular Determinants of Arterial Thrombosis

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Arterial thrombosis as the proximate cause of myocardial infarction, stroke, and limb gangrene remains the most important cause of mortality and morbidity in the USA. Blood platelets play a critical role in initiating arterial thrombi. The overall goal of this SCCOR is to discover genetic and cellular determinants of altered platelet function in systemic inflammatory states, such as atherosclerosis and diabetes. We have assembled a multidisciplinary team of clinical, basic and translational scientists and developed a Center with 6 scientific projects and 6 cores. Project 1 will use in vitro assays, in vivo mouse genetic models, and human genetic studies to examine the novel hypothesis that platelet glycoprotein CD36 mediates platelet hyper-reactivity associated with atherosclerosis, diabetes, and inflammation. Project 2 will explore a critically important clinical problem, platelet resistance to pharmacologic interventions, and will utilize a targeted human genetic approach coupled to sophisticated in vitro assessment of platelet function. Project 3 will explore the mechanistic role of platelet activating factor (PAF) in mediating the interface between inflammation and thrombosis. Project 4 will study a clinical population of patients undergoing endovascular carotid stenting as a model of the vulnerable plaque, focusing on developing novel imaging tools and biomarkers. Project 5 will study leukocyte-platelet interactions, focusing on the role of the Mac-1 integrin in regulating thrombosis. Project 6 will study patients with anti-phospholipid syndrome, an autoimmune disease that is an important cause of thrombosis, especially in young women, to characterize determinants of thrombotic risk. Core A will provide administrative support, Core B biostatistics support and Core C an infrastructure to support the clinical research components of all 6 projects. Core D will provide high throughput human genotyping services and Core E flow cytometry and mass spectrometry services. Core F will provide a curriculum and career development support for physicians training in clinical thrombosis research in SCCOR laboratories.