(from the application): This R03 Proposal focuses on the pathogenesis of cutaneous vascular lesions and associated angiogenesis. Hemangiomas are the most common cutaneous vascular lesions of childhood, and are present in 10% of infants at l year of age. These hemangiomas may grow to large size, resulting in compression of vital structures, high output cardiac failure, and coagulopathy. The coagulopathy phenomenon is known as the Kasabach-Merritt syndrome. Treatment of large hemangiomas requires lengthy treatment with steroids or alpha interferon, and surgery. A significant number of these hemangiomas do not respond to treatment, resulting in death. Little is known of the pathophysiology of these lesions, but preliminary evidence points to an imbalance of angiogenesis stimulators and inhibitors. We have developed a murine model of proliferative vascular lesions through the sequential introduction of SV40 large T antigen and H-ras into endothelial cells. This model recapitulates clinical and histologic features of both nonproliferative and proliferative hemangiomas. I wish to study the signal transduction pathways involved in upregulation of angiogenesis stimulators and downregulation of angiogenesis inhibitors. In addition, I have found that transformed endothelial cells express both VEGF and its receptor, flk-l, suggesting a possible autocrine loop. Interruption of these autocrine and paracrine loops may inhibit of the growth of endothelial tumors and potentially other neoplastic disorders. Finally, dominant oncogenes affect both angiogenesis and signal transduction pathways. Angiogenesis is likely regulated by signal transduction pathways, as is cell growth. Interruption of these signal transduction pathways may lead to effective therapy for tumors and other conditions by decreasing the amount of angiogenesis stimulators and/or increasing the amount of angiogenesis inhibitors.
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