TBX5 and Coronary Blood Vessel Development

描述(申请人提供)：TBX5转录因子在心脏结构的建立中起着关键作用，而TBX5突变会导致人类先天性心脏病。我们已经证明，Tbx5在鸡心外膜和冠状血管的胚胎建立过程中，在心外膜细胞的迁移中起着关键作用。在人胚胎组织中，TBX5在心外膜和冠状动脉血管壁高表达，但在从心外膜剥离形成冠状动脉的心外膜下细胞中表达失活。初步数据还表明，心前膜中Tbx5的活性上调了Ets-2的表达，Ets-2是一种转录因子，也参与了冠状动脉血管生成。然后，我们假设Tbx5依赖的涉及Ets-2的转录电路在胚胎发育过程中的心前膜、心外膜和冠状血管发育中发挥关键作用。此外，由于我们已经证明Tbx5活性在分化为血管母细胞的成人人和小鼠骨髓来源的干细胞中重新表达，我们假设Tbx5可能通过Ets-2激活来改变成人内皮前体细胞的分化，从而可能参与细胞介导的成人缺血心脏的血管重建。在这一应用中，我们建议利用鸡和小鼠实验模型：(1)确定Tbx5在心外膜和冠状动脉建立中的作用；(2)确定Tbx5在心外膜衍生物中对ETS-2表达的影响以及ETS-2在心外膜发育和冠状动脉血管生成过程中对Tbx5信号的贡献；(3)确定Tbx5在成年哺乳动物骨髓来源干细胞向血管母细胞分化过程中的作用。这些研究将突出冠状动脉血管前体细胞行为的关键转录调节因子，并将阐明冠脉血管形成的基本机制，以及培育新的靶点，以促进缺血性心肌病患者心脏组织的血运重建。

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.