The overall objective of this long-standing proposal is to develop a broad understanding of the basic molecular and cellular mechanisms that govern fibrinolysis. The degradation of fibrin is essential for maintenance of vascular patency and the restoration of homeostasis following coagulation. The pathophysiologic consequences of abnormal fibrinolysis range from thrombosis to bleeding diatheses. Plasmin is the primary enzyme responsible for degradation of fibrin in vivo. As a protease with broad recognition specificity, it can also degrade a variety of other substrates including circulation proteins, insoluble matrix constituents and cell surface molecules. Plasmin, therefore, contributes to diverse physiologic processes such as embryogenesis, histogenesis and cell migration, and pathophysiologic processes such as inflammation, tumor cell invasion and metastasis. Recently, a novel mechanism for the regulation of plasmin activity interaction of the zymogen, plasminogen, and enzyme, plasmin, with specific cell-surface binding sites. Data has now been developed to clearly establish the existence of these receptors, to provide an initial characterization of their plasmin(ogen) with cell surfaces provides a mechanism for the regulation of plasmin activity. In the forthcoming proposal, the interactions of plasminogen with cells will be explored in detail. 1) The cellular plasminogen binding sites will be isolated and characterized and the basis for their recognition of plasminogen and plasmin derivatives will be dissected. 3) Cellular events and responses which modulate the interaction of plasmin(ogen) with cells and, thereby, modulate plasmin activity will be examined. 4) The functional consequences of plasmin(ogen) binding to cell surfaces will be assessed in terms of the regulation of plasmin activity and in terms of initiating cellular responses and mediating cellular functions. On an overall basis, the proposed studies will continue to provide basic insights into the complex interface between cells and fibrinolysis, an interplay that is central to hemostasis, thrombosis and bleeding disorders.
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