This Career Development Award Proposal focuses on the pathogenesis of cutaneous vascular lesions. Hemangiomas are the most common cutaneous vascular lesions of childhood, and are present in 10 percent of infants at 1 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-1, suggesting a possible autocrine loop. Finally, the novel angiogenesis inhibitor endostatin has been isolated from a spontaneous hemangioendothelioma cell line. Its mechanism of action is unknown. I hope to learn the signal transduction pathways through which endostatin mediates angiogenesis inhibition. Interruption of angiogenic autocrine loops and targeting of signal transduction pathways activated in proliferative vascular lesions may provide novel therapies for hemangiomas. The Folkman laboratory has extensive experience in the isolation and characterization of angiogenesis stimulators and inhibitors. In order to become an independent investigator in angiogenesis, proficiency in these techniques is necessary. The opportunity to carry out the studies outlined in this proposal and receive formal training in cell biology, protein purification and characterization, and surgical procedures will afford the applicant the training which is required toward the establishment of his career as an independent physician-scientist.
