Functional analysis of Tgfbm3 locus in vascular development and disease

描述(申请人提供)：转化生长因子b1(TGFb1)信号通路在临床上非常重要。它直接与几种出生缺陷有关，包括马凡综合征、遗传性出血性毛细血管扩张症(HHT)、Camurati-Engelmann病和腭裂，还参与了影响人类的两种最重要的多因素疾病的病因学，即癌症和心血管疾病。TGFb1也是免疫调节的关键调节因子。编码包括TGFB1在内的TGFb1信号通路成分的基因在人类中已被证明是功能多态的，并且已发现特定TGFB1多态变异的携带者与癌症、动脉粥样硬化、心肌梗死、高血压和其他心血管疾病的易感性之间存在遗传关联。这项研究的目的是识别和表征影响体内TGFb1活性的基因变体的不同功能，特别是在血管生成和心血管疾病方面。这项建议的具体目标是确定小鼠12号染色体上TgfbmS基因座内负责遗传修改的变异的特征，并确定它们在血管生物学中的作用，以及2p25.1上的同源基因在人类ML风险中的作用。这些信息：a)将增加我们对TGFb1介导的血管重塑所涉及的分子通路的了解，b)可能为评估已知与TGFB1相关的疾病的疾病风险提供筛查工具c)将为此类疾病的预防药物开发提供靶点d)可能为抗TGFb药物治疗的反应提供预测性标记物

DESCRIPTION (provided by applicant): 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