This is an application to form a new SCOR program devoted to the pathology of human atherosclerosis. The proposal consists of six projects drawn from the Department of Pathology, Hematology, Laboratory Medicine, Biochemistry, and Genetics. Each is centered around testing a specific existing hypothesis that attempts to explain the origins of atherosclerotic lesions or the progression of these lesions to a clinically significant, life- threatening vascular obstruction. The projects are drawn together by a core laboratory devoted to the pathology of the human lesion. The first focus of the SCOR is in tests of the major current theories of the origin of plaque smooth muscle cells. The possibility that plaques begin with a viral mutagenic event is studied by a systematic search for plaque viri and study of the virology of vessel wall cells. The possibility that plaques originate developmentally is explored by an attempt at cloning genes whose expression is unique to the atherosclerotic plaque. Monoclonality of the lesion is studied at a new level using X- linked RNA polymorphisms to determine when and how monoclonality arises. The possibility that plaques originate as an inflammatory process is examined by looking at the role of plaque macrophages in expressing growth factors. All of these studies are carried out in human tissue. Tests of the hypotheses will depend on our ability to demonstrate the expected results in the human lesion. The second area of focus, studies of plaque progression, also emphasize the study of inflammatory mechanisms in the human lesion. Two projects include studies of the control of cytokine production by plaque macrophages and control of expression of leukocyte adhesion molecules. In addition to studies of the inflammatory process, one project is directed at lipoprotein lipase. The plaque macrophage, as well as the smooth muscle cell, are both studied as sources of lipoprotein lipase, an enzyme necessary to form free fatty acids. The project examines the control of expression of this enzyme by lineage-specific-cis-acting elements and elements responding to hormone factors. Finally, the SCOR proposes a new and unique approach to therapy of plaque pro-coagulant events by proposing use of a recombinant form of annexin, a phosphotidyl-serine binding protein, as an anticoagulant able to localize at sites of thrombosis.
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