TBX5 and Coronary Blood Vessel Development

TBX5 与冠状血管发育

• 批准号: 7014570
• 负责人: CRAIG T BASSON
• 金额: $ 41.01万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014570
• 关键词: RNA interference; angiogenesis; cell differentiation; cell migration; chick embryo; coronary vessels; developmental genetics; embryogenesis; gene expression; genetic regulation; genetically modified animals; hematopoietic stem cells; in situ hybridization; laboratory mouse; pericardium; transcription factor; transfection /expression vector

DESCRIPTION (provided by applicant): The TBX5 transcription factor plays a critical role in establishment of cardiac structure, and TBX5 mutations cause human congenital heart disease. We have demonstrated that Tbx5 plays a critical role in chick proepicardial cell migration during embryonic establishment of the epicardium and coronary vasculature. In human embryonic tissue, TBX5 expression is high in the epicardium and coronary vascular wall but is inactivated in the subepicardial cells delaminating from the epicardium to form coronary vessels. Preliminary data also suggest that Tbx5 activity in the proepicardium upregulates expression of the Ets-2, a transcription factor that has also been implicated in coronary vasculogenesis. We then hypothesize that Tbx5-dependent transcriptional circuits involving Ets-2 play critical roles in proepicardial, epicardial and coronary vessel development during embryogenesis. Furthermore, because we have shown that Tbx5 activities is re-expressed in adult human and murine bone-marrow derived stem cells differentiating into angioblasts, we hypothesize that Tbx5 can modify adult endothelial precursor cell differentiation, potentially via Ets-2 activation, and may thereby participate in cell mediated revascularization of the adult ischemic heart. In this application, we propose to utilize chick and mouse experimental models: (1) To determine the contributions of Tbx5 to establishment of the eppicardium and coronary vessels; (2) To define the impact of Tbx5 on Ets-2 expression in the proepicardial derivatives and the contribution of Ets-2 to Tbx5 signaling during epicardial development and coronary vasculogenesis; (3) To determine the role of Tbx5 expression during angioblastic differentiation of adult mammalian bone marrow derived stem cells. These studies will highlight critical transcriptional regulators of coronary vascular progenitor cell behavior and will both shed light on fundamental mechanisms that underlie the development of the coronary vasculature as well as foster novel targets to promote the revascularization of cardiac tissue in individuals with ischemic cardiomyopathies.

描述（由申请人提供）：TBX5转录因子在心脏结构的建立中起着至关重要的作用，而TBX5突变引起人类先天性心脏病。我们已经证明，TBX5在胚胎的胚胎养殖和冠状动脉脉管系统的胚胎建立过程中起着至关重要的作用。在人类胚胎组织中，心外膜和冠状动脉血管壁中的TBX5表达很高，但在上皮下细胞中被灭活，从胸膜上皮上分离到形成冠状动脉血管。初步数据还表明，胸膜内膜中的TBX5活性上调了ETS-2的表达，ETS-2是转录因子，也与冠状动脉血管发生有关。然后，我们假设涉及ETS-2的TBX5依赖性转录电路在胚胎发生过程中在心膜外，心外膜和冠状血管发育中起关键作用。此外，由于我们已经证明了TBX5活性在成年人和鼠骨髓中衍生成血管细胞的干细胞被重新表达，因此我们假设TBX5可以通过ETS-2激活来修改成人内皮前体细胞分化，并可能通过ETS-2激活，从而可以参与细胞介导的介导的成年成年成年ischemictematimematematemation ischematimemation。在此应用中，我们建议利用小鸡和小鼠实验模型：（1）确定TBX5对建立epperary和冠状动脉血管的贡献； （2）定义TBX5对eTS-2表达在心膜衍生物中的影响，以及在心外膜发育和冠状动脉血管发生过程中ETS-2对TBX5信号传导的贡献； （3）确定TBX5表达在成年哺乳动物骨髓衍生的干细胞的血管细胞分化中的作用。这些研究将重点介绍冠状动脉祖细胞行为的关键转录调节剂，并将揭示基本机制，这些机制是冠状动脉脉管系统发展的基础，以及促进缺血性心肌病个体心脏组织血运重建的新型靶标。