Aortic aneurysms, aortic dissections and cerebral aneurysms are vascular conditions that cause premature deaths. These deaths are completely preventable if individuals are diagnosed and surgical repair of the diseased aorta or artery performed. These deadly vascular diseases are inherited in families, primarily in an autosomal dominant manner with decreased penetrance and variable expression. The goal of the research program in my laboratory is to identify the genes that predispose individuals to aortic aneurysms, aortic dissections and cerebral aneurysms to prevent premature deaths, identify pathways leading to these vascular diseases and establish improved therapeutics and biomarkers for the disease. To achieve these goals, we are recruiting and characterizing families with multiple members with aortic aneurysms and dissections, along with cerebral aneurysms, and using DNA collected from these families to map and identify genes leading to these diseases. We currently have over 350 families participating in our studies. Using these families, we have mapped 4 loci for familial thoracic aortic aneurysms and dissections (TAAD) and identified the defective gene at one of these loci as the transforming growth factor beta type II receptor (TGFBR2). Identification of this defective gene as a cause of this disease has highlighted the role of TGF-beta signaling as a pathway leading to vascular disease. In addition, we have identified mutations in the smooth muscle cell myosin heavy chain gene (MYH11) as a cause of familial aneurysms and dissections, raising the possibility that defects in the sarcomere complex also lead to this disease. The research in my laboratory has three components. The first component is involved in recruiting and characterizing families with multiple members with vascular disease, specifically aortic aneurysms and dissections and cerebral aneurysms. A second component is focused on mapping genes causing familial vascular disease and identifying the defective gene at mapped loci. Finally, the third component uses cell biology to understand how defective genes alter smooth muscle cell function, in particular focusing on pathway analysis. In addition, the third component is involved in proteomic analysis to identify potential biomarkers for this disease.