Atherosclerosis is the major cause of cardiovascular disease, which is the leading contributor to mortality and morbidity in the United States. Risk factors associated, with atherosclerosis include,;type 2-diabetes. and hypertension. Elevated plasma levels of the serine protease inhibitor, plasminogen activatoMnhibitor-1, (PAI- 1) are correlated with these'risk factors and:several other thrombotic disorders..PAI-1.is the-.main regulator of the fibriholysis system, and is implicated as';a major player in the;pathopnysiology of cardiovascular disease, Plasminogen activator inhibitor-1 contains three major functional domains: 1) the.active.site region;2) the vitronectin binding site;, and 3). the;ic-w-density.lipopr.btein receptor related protein site..'these domains , . contribute either jointly or individually to PAI-1's role, in atherosclerosis and.vascular disease. I propose to. develop aptamers to. the three PAI-1 functional domains (SA I), and determine the effects, of these aptamers on endothelial cell function (SA II). Finally, I will assessIheir ability to regulate .thrombosis and angiogenesis;in vivo, using two well characterized mouse model systems (SA III). My research proposal/integrates my., background in biochemistry and molecular biology with vascular inflammation;and..in vivo animal studies.;This will greatly facilitate my long term career goal to become an independent investigator in the .field of . ',-. hemostasis and thrombosis. Over the next five years, I wish to expand my basic'science.knowledge in the area of thrombosis and coagulation. I also aspire to improve my ability to develop hypotheses and design experiments to test my hypotheses, as well as to acquire more technical skills to conduct in vivo animal studies. Gaining additional knowledge.;in these areas will facilitate my promotion to associate professor. Dr. Charles Lowenstein, a widely recognized authority on vascular endothelial function will provide invaluable mentorship throughout my career development. John Hopkins University and its vast institutional and personnel resources, provides an ideal setting in which to conduct the biomedical research I propose. My advisory committee consists of Dr. Frank Church, Dr. Gregg Semenza, and Dr. Janice Clements, all of whom have excelled in their fields and who have exceptional credentials as investigators and mentors.
. Understanding the physiological function of PAI-1, and the mechanism underlying its function under normal and pathological conditions, is necessary to develop strategies to treat and prevent cardiovascular events in high risk patients. Consequently, abatement of PAI-1's function will be a beneficial therapeutic option for the treatment and prevention of PAI-1 associated vascular events. This is particularly important, since to date, there are no PAI-1 inhibitors available for clinical use
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