Pathological Consequences of the Plasminogen System

University Of Notre Dame, Notre Dame IN

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Abstract

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to identify functions and determine mechanisms of the fibrinolytic system, and its inhibitors, in physiological and pathophysiological processes utilizing in vivo models. The contribution of the fibrinolytic system in hemostasis, through the capacity of plasmin to catalyze degradation of fibrin, has been extensively studied in both in vitro and in vivo models. The identification of receptors for components of the fibrinolytic system on a number of cell surfaces implicates plasmin as playing a role in cell migratory events. The availability of mice with single and multiple deficiencies of genes encoding components of the fibrinolytic system have resulted in direct analyses of the role of these proteins in a number of physiological and pathological events. Previous studies have demonstrated dramatic effects of deficiencies of these proteins in atherosclerosis, pulmonary fibrosis, skin wound healing, tumor growth, and angiogenesis. Due to the impact of a PAl-1 deficiency on vascular injury/repair, tumor growth, angiogenesis, and wound healing, studies described in this application will focus on the following studies: 1.) Since a PAl-1 deficiency diminishes angiogenesis, the effects on endothelial cell proliferation, migration, sprouting, directed migration, apoptosis, and expression of angiogenic regulatory molecules will be studied utilizing PAl-1-/- endothelial cells. 2.) Determine whether the PAl-1 effects on angiogenesis are mediated through alterations in cell adhesion, inhibition of plasminogen activator function, or uPA-mediated cell signaling by generating mice expressing mutated PAl-1 proteins and challenging these mice with models with phenotypes associated with an angiogenic response. 3.) Further characterize functional deficits of endothelial cells derived from mice described in Aim 2 utilizing analyses described in Aim 1.