TGFBM2 in Development and Disease

描述（由申请人提供）：转化生长因子β信号通路与许多被认为是多因素病因的常见疾病密切相关，包括癌症、心血管疾病、哮喘、纤维化和炎症。人类遗传学也显示了与几种出生缺陷的直接关系，包括Loeys- Dietz综合征、Marfan综合征、Camurati-Engelmann病和遗传性出血性毛细血管扩张症，所有这些都是由单个tgf通路基因的突变引起的。然而，tgfβ的作用高度依赖于环境，依赖于基因变异之间的遗传相互作用。因此，tgfb相关疾病的表型谱是高度可变的。利用小鼠和人类遗传学，我们在小鼠远端1号染色体人类1q41上发现了一个基因位点TGFBM2，它影响Tgfb1KO小鼠和人类遗传性出血性毛细血管扩张症（HHT）中tgfβ信号遗传减少的表型结果。我们已经将这种遗传变异定位到TGFBM2中的一个特定基因，该基因与荷兰HHT患者动静脉畸形的出现有关。当前项目的目标是在法国高加索HHT家族的独立人群中复制人类遗传关联研究，并更精细地绘制人类遗传变异区域。我们将在携带TGFBM2变异基因的小鼠胚胎成纤维细胞中使用体外siRNA检测TGFBM2基因和TGFB信号通路之间的功能相互作用。我们将通过基因转染研究和体外蛋白结合研究来研究TGFBM2和TGFB信号之间相互作用的分子机制。我们将利用现有的和新的TGFBM2和TGFB1 KO小鼠验证TGFBM2和TGFB信号之间的体内相互作用。最后，我们将在体外研究TGFBM2与HHT中涉及的BMP/ENG/ACVRL信号通路的相互作用，并通过将TGFBM2基因和基因敲除小鼠与engko小鼠杂交。这一信息将增加对体内调节TGFB生物学的遗传相互作用的理解，加深对PAVM易感性的理解，特别是对血管疾病的易感性。

DESCRIPTION (provided by applicant): 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.