TBX5 and Coronary Blood Vessel Development

描述（由申请人提供）：TBX 5转录因子在心脏结构的建立中起关键作用，TBX 5突变导致人类先天性心脏病。我们已经证明，Tbx 5起着至关重要的作用，鸡前心外膜细胞迁移在胚胎建立的心外膜和冠状动脉血管。在人胚胎组织中，TBX 5在心外膜和冠状血管壁中表达高，但在从心外膜分层以形成冠状血管的心外膜下细胞中失活。初步数据还表明，Tbx 5在前心外膜中的活性上调了Ets-2的表达，Ets-2是一种转录因子，也与冠状动脉血管发生有关。然后，我们假设Tbx 5依赖的转录电路涉及Ets-2发挥关键作用，在胚胎发育过程中的心外膜，心外膜和冠状血管的发展。此外，因为我们已经表明Tbx 5活性在分化为成血管细胞的成人和小鼠骨髓来源的干细胞中重新表达，所以我们假设Tbx 5可以潜在地通过Ets-2活化来修饰成人内皮前体细胞分化，并且可能因此参与成人缺血心脏的细胞介导的血管重建。本研究拟利用鸡和小鼠实验模型：（1）确定Tbx 5对心外膜和冠状动脉血管建立的作用;（2）确定Tbx 5对前心外膜衍生物中Ets-2表达的影响以及Ets-2在心外膜发育和冠状动脉血管发生中对Tbx 5信号传导的作用;（3）探讨Tbx 5在成体哺乳动物骨髓源干细胞向血管样细胞分化过程中的作用。这些研究将突出冠状动脉血管祖细胞行为的关键转录调节因子，并将揭示冠状动脉血管系统发育的基本机制，以及培养新的靶点，以促进缺血性心肌病患者心脏组织的血管重建。

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.