Abnormalities in the plasminogen activator system have been implicated in the pathogenesis of arterial and cerebral thrombosis. In particular, elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), and t-PA/PAI-1 complexes have been found to correlate with increased risk of myocardial infarction (MI) and/or stroke. Vascular fibrinolytic balance is, to a large part, determined by the competing effects of t-PA and PAI-1, and reflects a complex interplay between genetic and environmental factors. The present collaboration focuses on the common hypothesis that the association between activation of the renin-angiotensin- aldosterone system (RAAS) and atherothrombotic events derives from an interaction between the RAAS and the fibrinolytic system. The collaborative team that we have assembled to test this hypothesis includes investigators from 3 continents (America, Europe, and Africa), from 5 academic institutions (Meharry Medical College, Vanderbilt University Medical School, University of Groningen, University of Michigan and University of Ghana) and from multiple departments within these institutions. The individual investigators bring to this collaboration diverse and complementary skills in molecular biology, vascular biology, hypothesis-driven patient-oriented research, human genetics, and clinical and genetic epidemiology. The proposal is comprised of 4 complementary projects: 1) Molecular Genetics of PAI-1 Expression, 2) Genes and Fibrinolytic Capacity of Human Endothelium, 3) Genetic Architecture of Plasma t-PA and PAI-1, and 4) Genetic Variants and Thrombosis: The Renin-Angiotensin and Fibrinolytic Systems. The proposed molecular genetic methods, new transgenic mouse models, mechanistic human studies, and innovative study designs in genetic epidemiology promise to provide complementary data. Data derived from these studies are expected yield new information regarding the mechanism of interaction of the RAAS and fibrinolytic systems. The collaboration takes advantage of existing DNA samples collected from American, European, and African population studies and intervention trials to test the hypothesis in groups of different ethnic background and cardiovascular risk. These population- based studies are expected to generate new hypotheses to be tested at the molecular level in cells and at a physiological level in humans. This collaborative proposal provides a robust mechanism for highly focused translational research in the molecular genetics and biology of the role of the fibrinolytic system in arterial and cerebral thrombosis.
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