Modulating the resolution of angiogenesis and normalization of the vasculature for therapeutic benefit

The proposed research will investigate the fundamental processes regulating the resolution of angiogenesis, focusing on the membrane-anchored serine protease, testisin. Strong preliminary data suggest testisin is a novel proteolytic orchestrator of microvascular endothelial cell remodeling, promoting VE-cadherin inter-junctional adhesions, suppressing a proangiogenic signaling pathway, and directing fibrin matrix deposition for reparative angiogenesis. The research plan will utilize molecular biology, biochemistry, and cell biology techniques, in concert with several in vivo mouse models, to address two specific aims: 1) to define mechanisms by which testisin deficiency impairs resolution of angiogenesis, and 2) to test the therapeutic efficacy of augmenting the testisin pathway to promote resolution of angiogenesis. The findings are expected to inform treatments for diseases perpetuated by unresolving or insufficient angiogenesis and to enhance the effective delivery of cancer therapeutics.