This application focuses on the mechanisms or pathogenesis or hemangiomas and associated angiogenesis. Hemangiomas are the most common cutaneous vascular lesions of childhood, and are present in 5 percent of infants at 1 year of age. These hemangiomas may grow to large sizes and may result in compression of vital structures or high output cardiac failure. Treatment of large hemangiomas requires lengthy treatment with steroids or alpha interferon, and surgery. These treatments are associated with a high level of morbidity, including growth retardation, infection, and irreversible neuropathy. A significant number of these hemangiomas do not respond to treatment, resulting in death. The signal transduction pathways that underlie these lesions are not completely understood. Hemangiomas are a reactive process associated with an imbalance in the angiogenic switch, resulting in the proliferation and migration of host endothelial cells to an angiogenic stimulus (host recruitment). This process may involve autocrine and paracrine loops between endothelial specific ligands and their receptors on normal endothelial cells. The principal investigator has developed a mouse model of hemangiomas, using the murine neonatal endothelial cell line A9519. This model recapitulates the clinical and histologic characteristics of human hemangiomas. Previous studies performed by our laboratory have shown that activation of a single signal transduction pathway, phosphoinositol-3-kinase, is critical for the regulation of angiogenesis in SYR cells, which are derived from adult murine endothelium through the sequential introduction of SV4O large T antigen and H-ras. We believe that activation of both the mitogen activated protein kinase (MAPK) and phosphoinositol-3-kinase (PI-3.-kinase) pathways are required for growth of benign hemangiomas in mice and humans. Inhibition of these pathways provides therapeutic possibilities for the treatment of hemangiomas and other cutaneous angiogenic disorders. Hypothesis: Activation of both MAPK and P1-3-kinase pathways is required for hemangioma growth in vivo.
Specific Aim 1. To determine the presence of autocrine loops in hemangioma cells in vitro and in vivo.
Specific Aim 2. To determine the role of activation of the MAPK and PI-3-kinase pathways in a murine model of hemangioma using dominant negative signal transduction genes and pharmacologic inhibition.
Specific Aim 3. To determine the identity and function of downstream effectors of MAPK and PI3-kinase in hemangiomas. The studies outlined in this proposal will contribute to our basic understanding of cutaneous angiogenesis. In addition, insights gained from the studies described in this proposal will lead to more accurate diagnosis of other endothelial neoplasms, such as hemangioendothelioma, Kaposi's sarcoma, and angiosarcoma, as well as lead to novel therapeutic approaches to cutaneous disease through signal transduction modulation.
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