Endothelial cells (EC) are in constant contact with all blood components and are critical for blood coagulation, platelet adhesion and aggregation, immune and inflammatory responses, and vascular remodeling. Dynamic changes in endothelial cell structure and function that are induced by proteases represent potential targets for therapeutic intervention. Our ultimate goal is to develop new therapeutic approaches for treatment of vascular pathologies by targeting EC surface proteolysis. In studies aimed at identifying new serine proteases that may govern angiogenesis, we. discovered Testisin as a glycosylphosphatidylinositol (GPI) -anchored protease that was expressed only in angiogenic vascular beds. New preliminary data show that Testisin is required for capillary formation during angiogenesis. Host Testisin deficiency in mice retards tumor growth and inhibits angiogenic responses. Testisin activity is linked to the coagulation cascade. We hypothesize that Testisin is a key participant in the regulation of capillary morphogenesis, an activity that impacts mechanisms of angiogenesis and EC barrier function. We expect that Testisin activity contributes to diseases associated with pathological angiogenesis and enhanced vascular permeability, specifically tumor growth, vascular diseases and inflammatory responses. The proposed studies will test the following hypotheses: 1) that Testisin participates in angiogenesis required to sustain tumor growth by contributing to capillary formation 2) that Testisin functions as a regulator of VEGF dependent angiogenic responses and 3) that Testisin mediates localized EC signal transduction and in doing so, contributes to increased EC paracellular permeability. These hypotheses will be tested in the following specific aims: (1) To determine the role of Testisin in tumor angiogenesis, (2) To determine the participation of Testisin in physiological and injury induced angiogenic responses, (3) To investigate the participation of Testisin in the regulation of vascular permeability. These studies will involve molecular and biological approaches, in vitro and in vivo animal models of angiogenesis and vascular permeability, cell migration assays and proteomics approaches. ? ? ?
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