) The major objective of this proposal is to test the hypothesis that a cryptic domain of collagen-IV plays a fundamental role in the regulation of angiogenesis and tumor growth. This proposal is based on a series on observations from experiments performed with a novel monoclonal antibody (Mab HUIV 26) directed to proteolyzed collagen-IV. Collagen-IV is a major component of the subendothelial basement membrane of blood vessels, and thus, endothelial cell invasion through this collagen-IV rich barrier likely contributes to neovascularization. Importantly, the possibility that biochemical regulatory information is hidden within the three dimensional structure of specific ECM molecules has not been explored in detail. In fact, little direct evidence is available concerning the mechanism by which ECM remodeling contributes to angiogenesis. To this end, our preliminary findings suggest that Mab HUIV26 specifically recognizes a cryptic domain in collagen- IV which is inaccessible within mature native collagen-IV but is exposed following proteolysis. Moreover, our finding suggest that this HUIV26 cryptic domain is specifically exposed within the subendothelial basement membrane of tumor associated blood vessel in vivo. Furthermore, preliminary results suggest that systemic administration of Mab HUIV26 inhibits angiogenesis and tumor growth. Based on these preliminary findings, it is possible that proteolysis of collagen-IV may represent a unique mechanism by which cryptic biochemical information is transferred to endothelial cells, thereby regulating angiogenesis and tumor growth. Thus, the identification and functional characterization of this cryptic domain, may lead to the development of novel therapeutic approaches for the treatment of pathological neovascularization and malignant tumor growth.
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