Functional analysis of Tgfbm3 locus in vascular development and disease

转化生长因子β 1（TGF β 1）信号通路在临床上非常重要。它直接 与几种出生缺陷有关，包括马凡氏综合征、遗传性出血性毛细血管扩张症、 (HHT)，Camurati-Engelmann病和腭裂，以及被卷入的病因，这两个 影响人类的最重要的多因素疾病，即癌症和心血管（CV）疾病。 TGF β 1也是免疫调节的关键调节因子。编码TGF β 1信号传导组分的基因 包括TGFB 1在内的信号通路在人类中具有功能多态性， 已发现特定TGFB 1多态性变体的携带者与疾病之间存在关联， 癌症、动脉粥样硬化、心肌梗塞（MI）、高血压和其他心血管疾病的易感性 疾病本研究的目的是确定和表征遗传的差异功能， 影响体内TGF β 1作用活性的变体，特别是关于血管生成和CV 疾病该提案的具体目标是表征负责遗传的变异。 小鼠12号染色体上TgfbmS基因座内的修饰，并确定它们在血管内皮细胞中的作用。 生物学，以及2p25.1处的正向同源基因在人类Ml风险中的作用。此信息：a）将 增加我们对TGF β 1介导的血管重塑所涉及的分子途径的理解，B） 可提供筛查工具，用于评估已知存在TGFB 1的疾病风险 c）将为此类疾病的预防性药物开发提供靶点d）可以提供 对抗TGF β药物治疗反应的预测标志物

The transforming growth factor b1 (TGFbl) signaling pathway is clinically very important. It is directly implicated in several birth defects, including Marfan Syndrome, Hereditary Hemorrhagic Telangiectasia (HHT), Camurati-Engelmann disease and cleft palate, as well as being involved in the etiology of the two most important multifactorial diseases affecting humans, namely cancer and cardiovascular (CV) disease. TGFbl is also a key regulator of immunomodulation. Genes encoding components of the TGFbl signaling pathway including TGFB1 have been shown to be functionally polymorphic in humans, and genetic associations have been found between carriers of specific TGFB1 polymorphic variants and disease susceptibility for cancer, atherosclerosis, myocardial infarction (Ml), hypertension and other cardiovascular diseases. The goal of this research is to identify and characterize the differential functions of genetic variants that influence the activity of TGFbl action in vivo, particularly with respect to angiogenesis and CV disease. The specific objective of this proposal is to characterize variants responsible for genetic modification within the TgfbmS locus on mouse chromosome 12 and to determine their role in vascular biology, and the role of orthologous genes at 2p25.1 in risk for Ml in humans. This information:a)Will increase our understanding of molecular pathways involved in TGFbl-mediated vascular remodeling, b) May provide screening tools for assessment of disease risk in ailments known to have a TGFB1 associationc) Will provide targets for prophylactic drug development of such diseases d) May provide predictive markers for response to anti-TGFb drug therapies