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关键作用，TBX5突变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心外膜前细胞迁移中起关键作用。在人胚胎组织中，TBX5在心外膜和冠状血管壁中高表达，但在心外膜脱层形成冠状血管的心外膜下细胞中失活。初步数据还表明，Tbx5在心外膜前的活性可上调Ets-2的表达，Ets-2是一种转录因子，也与冠状动脉血管形成有关。然后，我们假设tbx5依赖的转录回路涉及Ets-2在胚胎发生过程中心外膜前、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Tbx5活性在成人和小鼠骨髓干细胞分化成血管细胞中重新表达，我们假设Tbx5可能通过激活Ets-2来修饰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。在本应用中，我们拟采用鸡和小鼠实验模型：(1)确定Tbx5对心外膜和冠状血管建立的贡献；(2)明确Tbx5对心外膜前衍生物中Ets-2表达的影响，以及Ets-2在心外膜发育和冠状动脉血管形成过程中对Tbx5信号传导的贡献；(3)探讨Tbx5表达在成年哺乳动物骨髓干细胞成血管分化过程中的作用。这些研究将强调冠状动脉祖细胞行为的关键转录调节因子，并将阐明冠状动脉血管发育的基本机制，以及培养促进缺血性心肌病患者心脏组织血运重建的新靶点。

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.