Roles of Akt and immune regulation in the development of hemangiomas

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DESCRIPTION (provided by applicant): This proposal describes my research training program for the development of an academic career as a physician scientist. The Benjamin laboratory has extensive experience in studying the regulation of angiogenesis in development and tumorigenesis, and has developed unique tools to study signal transduction in endothelial cells in vivo. The opportunity to carry out the studies outlined in this proposal will provide the training necessary for me to become an independent physician scientist. My research goal is to understand the pathogenesis of cutaneous vascular lesions. Hemangiomas are the most common soft-tissue tumor of infancy, occurring in 5 to 10 percent of Caucasian infants. Despite the frequency and functional and physical impairment these vascular tumors can cause, little is known about their pathogenesis. In support of this proposal, I have preliminary data that implicate an important role of Akt in hemangioma formation, and have established a novel mouse model of hemangioma in response to inducible and endothelial cell-specific expression of constitutively active myristylated Akt (myrAkt). Furthermore, when crossed into immunodeficient athymic nu/nu background, myrAkt transgenic mice develop widespread hemangiomas in response to hyperactivated Akt. These findings implicate the role of immune regulation in hemangioma formation in this model. I hypothesize that sustained Akt activation in endothelial cells is sufficient for the development of hemangioma, and that hemangioma formation is modulated by the immune system. I will test these hypotheses as a first step in my long-term goal of designing therapy for children with disfiguring or life-threatening hemangiomas. My aims are to determine (1) whether loss of Akt and its downstream effector mTOR inhibits hemangioma formation; (2) whether activation of Akt through loss of PTEN is sufficient to form hemangioma; and (3) the role of immune regulation by T cells in the development of hemangiomas. The proposed studies will increase our understanding of how endothelial cell behavior is regulated, and help us better understand other vascular neoplasms, such as hemangioendothelioma and angiosarcoma, and open new therapeutic options in the treatment of vascular tumors through signal transduction modulation. (End of Abstract)