The transforming growth factor beta signaling pathway is strongly implicated in many common diseases considered to be multifactorial in etiology, including cancer, cardiovascular disease, asthma, fibrosis and inflammation. Human genetics has also shown a direct involvement in several birth defects, including Loeys- Dietz Syndrome, Marfan Syndrome, Camurati-Engelmann disease and Hereditary Hemorrhagic Telangiectasia, all caused by mutations in individual TGFbeta pathway genes. However, the action of TGFbeta is highly context-dependent, and depends on genetic interactions between gene variants. Thus the phenotypic spectrum of TGFB-associated diseases is highly variable. Utilizing mouse and human genetics, we have identified a genetic locus, TGFBM2, on distal mouse chromosome 1, human 1q41, that influences the phenotypic outcome of genetic reduction in TGFbeta signaling in the Tgfb1KO mice and in human Hereditary Haemorraghic Telangiectasia (HHT). We have mapped this genetic variation to a specific gene within TGFBM2 that is associated with appearance of arterio-venous malformations in Dutch HHT patients. The goals of the current project, are to replicate the human genetic association studies in an independent population of French Caucasian HHT families, and to more finely map the human region of genetic variation. We will validate a functional interaction between the TGFBM2 gene and the TGFB signaling pathway using in vitro siRNA assaysin mouse embryo fibroblasts derived from congenic mice that carry variants of TGFBM2. We will investigate molecular mechanisms of interaction between TGFBM2 and TGFB signaling using gene transfection studies and in vitro protein binding studies. We will validate the in vivo interaction between TGFBM2 and TGFB signaling utilizing existing and novel TGFBM2 and TGFB1 KO mice. Finally, we will examine the interaction of TGFBM2 with the BMP/ENG/ACVRL signaling pathway implicated in HHT, both in vitro, and by breeding TGFBM2 congenic and knock out mice to ENG KO mice. This information will increase understanding of genetic interactions that regulate TGFB biology in vivo, deepen understanding of predisposition to PAVM in particular, and to vascular disease in general. TGFB1 is a central player in many human diseases, and drug companies are now targeting this pathway for treatment of various diseases, including fibrosis and cancer, but its action depends on interactions with other genes. We have identified a gene that interacts with TGFB1 in mice and humans to alter vascular disease progression. Understanding how these molecules interact may ultimately help to design new or better drugs.