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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Krasnewich, Donna M
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Arnold, Thomas D; Niaudet, Colin; Pang, Mei-Fong et al. (2014) Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking ?V?8-TGF? signaling in the brain. Development 141:4489-99
Kawasaki, Kyoko; Freimuth, Julia; Meyer, Dominique S et al. (2014) Genetic variants of Adam17 differentially regulate TGF? signaling to modify vascular pathology in mice and humans. Proc Natl Acad Sci U S A 111:7723-8
Benzinou, Michael; Clermont, Frederic F; Letteboer, Tom G W et al. (2012) Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun 3:616
Connolly, Erin C; Freimuth, Julia; Akhurst, Rosemary J (2012) Complexities of TGF-? targeted cancer therapy. Int J Biol Sci 8:964-78
Lamouille, Samy; Connolly, Erin; Smyth, James W et al. (2012) TGF-?-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci 125:1259-73
Freimuth, Julia; Clermont, Frederic F; Huang, Xiaozhu et al. (2012) Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus. Proc Natl Acad Sci U S A 109:18042-7
Akhurst, Rosemary J; Hata, Akiko (2012) Targeting the TGF? signalling pathway in disease. Nat Rev Drug Discov 11:790-811
Akhurst, Rosemary J (2012) The paradoxical TGF-? vasculopathies. Nat Genet 44:838-9
Akhurst, Rosemary J (2010) Taking thalidomide out of rehab. Nat Med 16:370-2
Mao, Jian-Hua; Saunier, Elise F; de Koning, John P et al. (2006) Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility. Proc Natl Acad Sci U S A 103:8125-30

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