TGFBM2 in Development and Disease

描述（由申请人提供）：转化生长因子β信号通路与许多常见疾病密切相关，这些疾病被认为是多因素病因，包括癌症、心血管疾病、哮喘、纤维化和炎症。人类遗传学还显示出直接涉及几种出生缺陷，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 β途径基因的突变引起的。然而，TGF β的作用高度依赖于环境，并且取决于基因变体之间的遗传相互作用。因此，TGF β相关疾病的表型谱是高度可变的。利用小鼠和人类遗传学，我们已经确定了一个遗传基因座，TGFBM 2，在远端小鼠1号染色体，人类1 q41，影响表型结果的TGF β信号在Tgfb 1 KO小鼠和人类遗传性毛细血管扩张症（HHT）的遗传减少。我们已经将这种遗传变异映射到TGFBM 2内的一个特定基因，该基因与荷兰HHT患者动静脉畸形的出现相关。当前项目的目标是在法国高加索人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。我们将使用来自携带TGFBM 2变体的同源小鼠的小鼠胚胎成纤维细胞中的体外siRNA检测来验证TGFBM 2基因和TGFB信号通路之间的功能性相互作用。我们将使用基因转染研究和体外蛋白结合研究来研究TGFBM 2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TGFBM 2和TGFB 1 KO小鼠验证TGFBM 2和TGFB信号传导之间的体内相互作用。最后，我们将研究TGFBM 2与HHT中涉及的BMP/ENG/ACVRL信号通路的相互作用，包括体外和将TGFBM 2同源和敲除小鼠培育成ENG KO小鼠。这些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理解。 公共卫生相关性：TGFB 1是许多人类疾病的核心参与者，制药公司现在正在针对这一途径治疗各种疾病，包括纤维化和癌症，但它的作用取决于与其他基因的相互作用。我们已经确定了一个基因，与TGFB 1在小鼠和人类相互作用，以改变血管疾病的进展。了解这些分子如何相互作用可能最终有助于设计新的或更好的药物。

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.