MATRIXINS AND THEIR INHIBITORS IN ANGIOGENESIS

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DESCRIPTION: Angiogenesis is a fundamental process of new blood vessel formation. It is critical for development, reproduction, and wound healing. Uncontrolled neovascularization plays a role in cancer, rheumatoid, vascular and other diseases. Angiogenesis is essential for providing oxygen and nutrients for tumor growth and for generating a gateway for cancer cell metastasis. Angiogenesis inhibitors may become one of the most promising types of drugs for starving tumor cells and preventing the spread of cancer cells. Angiogenesis involves proteolytic digestion of the extracellular matrix proteins such as collagens underlying the blood vessel endothelial cell layers. The long term goals of this research are to elucidate the mechanisms by which new blood vessels are formed, to identify the role of collagen-degrading matrixins (matrix metalloproteinases, MMPs) including membrane-type I matrix metalloproteinases, MMPs) including collagenases/gelatinases (MMP-2, MMP-9), and interstitial collagenase (MMP-1), in angiogenesis. The following two hypotheses will be tested. First, under angiogenic conditions, such as in the presence of vascular endothelial growth factor and/or basic fibroblast growth factor, endothelial cells will produce collagen degrading matrixins to break down type I and IV collagens. The role of each collagen-degrading matrixin in human microvascular endothelial cell -mediated collagen dissolution will be dissected with highly selective, potent, and novel synthetic inhibitors of matrixins. Second, collagen-degrading matrixins are required for angiogenesis and they may regulate endothelial cell proliferation, migration, and tube formation. The role of each collagen-degrading matrixin in each step of angiogenesis in vitro will be assessed through intervention by the synthetic matrixin inhibitors.