All tumors must overcome an angiogenic barrier as they progress to malignancy. This barrier is maintained by a variety of molecules that are natural inhibitors of angiogenesis and serve to block the sprouting of new blood vessels in most normal adult tissues. The PI has recently discovered a new and exceptionally potent natural inhibitor of angiogenesis that is highly expressed in the normal retina , but lost in several pediatric tumors and identified it as a 50 kDa protein that had been previously cloned in another context. This proposal outlines experiments designed to understand how this inhibitor works, how it is regulated during tumor progression and what role it plays in the angiogenesis associated with childhood malignancies and in eye diseases. The mechanism by which the new inhibitor blocks angiogenesis will be identified along with the site on the protein that mediates its anti-angiogenic activity. This new inhibitor is unique among the previously identified inhibitors in that its production by cells is inhibited by hypoxia, so the mechanism underlying this suppression will be studied to determine if it is widespread, if it is dependent on an oxygen sensor and to learn the molecular level at which control is exerted. To determine the general function of this protein, a mouse expressing beta-galactosidase in its place is being produced and will be used to investigate expression patterns and effects of loss of the inhibitor on gross and microscopic anatomy, on normal vascular development, and on tumorigenesis. Finally the expression of the anti-angiogenic protein will be examined in a murine model of retinopathy and in neuroblastoma tumors and its ability to control the angiogenic phenotype of primary tumors, their explants and tumor cell lines determined. These experiments will enhance our understanding of how tumors develop and maintain their essential angiogenic phenotype. They have the exciting possibility of defining a new anti-angiogenic agent capable of controlling the growth of vessels that feed malignant tumors and cause the devastating ocular angiogenesis that is a leading cause of blindness.
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