Molecular Genetics of Coagulation Disorders

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DESCRIPTION (provided by applicant): Abnormalities in the regulation of coagulation and thrombosis play a major role in the pathogenesis of many heart, lung, and blood diseases. This Program Project will integrate the research efforts of a number of independent investigators to explore the molecular basis for selected disorders of coagulation and thrombosis and the role of hemostatic balance in vascular disease pathogenesis. The PPG builds on the existing strength at the University of Michigan in human molecular genetics and cell and molecular biology of blood coagulation. The individual projects in this proposal emphasize the use of new technologies to provide improved biologic insight and develop new treatments for hemorrhage, thrombosis and related cardiovascular disorders. The four individual projects contained in this PPG will: 1) employ a whole genome ENU mutagenesis scan in an effort to identify a large panel of modifier genes for factor V Leiden in the mouse as candidate genes contributing to thrombosis susceptibility in humans with factor V Leiden and other prothrombotic disorders; 2) explore the role of ER processing in coagulation FV and FVIII biosynthesis to identify the molecular basis for combined deficiency of factor V and factor VIII, and examine the role of altered FVIII level as a risk factor for thrombosis; 3) and 4) study the contribution of the fibrinolytic system components PAI1 and vitronectin to the pathogenesis of atherosclerosis (3) and the pathologic response to vascular injury leading to neointimal hyperplasia (4), and the potential of this system as a target for therapeutic intervention. The PPG will support the development of 4 cores: A) the Mouse Coagulation Laboratory; B) the Genetics Core; C) the Administrative Core, and D) the Morphology Core. The PPG will aim to increase interaction and collaboration between individual project participants, as well as among the large number of other laboratories at the University of Michigan already engaged in research on coagulation, thrombosis and vascular disease. We anticipate that the overall program resulting from the combined efforts of all participants will significantly exceed the sum of the individual parts.