This Program Project application, entitled Molecular and Cellular Mechanisms of Vascular Anomalies requests continued funding for collaborative efforts of three research groups, two in Boston, and one in Brussels, Belgium to elucidate pathogenetic mechanisms of human vascular anomalies, to generate mouse models and identify therapeutic targets. These common vascular disorders belong to the group of childhood conditions popularly known as vascular birthmarks. One in about 100 children born have a vascular birthmark, and although significant progress has been made in identifying the genetic basis for many of the more rare forms of these anomalies, they are frequently misdiagnosed and effective therapies are unavailable. To advance pathogenetic understanding of vascular anomalies, provide the basis for better molecular diagnostic tools and development of new rational therapies, the investigators propose to continue their research on infantile hemangioma, a vascular tumor found in 10% of Caucasian children at 1 year of age, and venous malformations through highly interactive program consisting of three Projects and three Cores. Hemangiomas usually appear a few days after birth, grow rapidly for a few weeks to months, and then slowly regress over a 5-10-year period. Malformations do not regress, but grow with the child and can become life-threatening. Building on discoveries made during the first grant period and taking advantage of exceptional patient-data, tissue, cell and nucleic acid resources that have been collected in two Cores, one in Boston and one in Brussels, the investigators propose to use genetic, cell biological, and protein chemistry techniques to gain deeper understanding of how gene mutations that are associated with hemangioma and venous malformations affect endothelial and smooth muscle cell differentiation and function. Animal models comprising human cells transplanted into immunocompromised mice and genetically modified mice carrying hemangioma- and venous malformation-associated mutations will be characterized and used for testing hypotheses and explored for preclinical trials of disease-modifying drugs.