Notch信号通路在第二心区发育中的调控机制研究

Congenital heart disease (CHD) is one of the leading birth defects, caused by abnormal early heart development. The mammalian heart derives from two heart fields, first heart field (FHF) and recently discovered secondary heart field (SHF). Cardiac progenitors from SHF migrate to the FHF and later differentiate to constitute a major cellular component of heart. The underlying molecular mechanism regulating the SHF progenitors proliferation, differentiation, migration is still unknown. Notch singaling pathway plays an important role in heart development, regulating right ventricle, outflow tract and cardiac valves normal formation. Using mouse genetic model, yeast hybridization screening and co-immunoprecipitation technologies, we will test the role of Notch signaling key transcription factor in early heart development, and try to unveil the molecular mechanism of the transcriptional control of SHF caridac progenitor proliferation and differentiation. This study would not only help us understand the molecular regulatory machinary in the normal heart development, but also provide theoratical basis for etiology and therapy of congential heart disease.

先天性心脏病是最常见的出生缺陷，导致其发生的直接原因是心脏早期发育异常。心脏的发育起源于心脏第一心区（First heart field，FHF）和第二心区（Second heart field，SHF）。SHF参与了心脏大部分细胞的形成，了解信号分子在心脏SHF中的调控机制非常重要。Notch信号通路对心脏发育有重要调控作用，它调控右心室、流出道、心脏瓣膜等的正常形成。在此基础上，我们采用基因敲除、酵母双杂交和免疫共沉淀等技术对Notch信号通路调控SHF心脏祖细胞的分子机制进行研究，以阐明它如何调控SHF心脏祖细胞增殖分化和迁移，探索Notch信号通路中转录因子协同调节蛋白调控靶基因的分子机制。该研究将帮助我们深入了解心脏发育的分子调控机制，为先天性心脏病的防治提供坚实的理论基础。

先天性心脏病是最常见的出生缺陷，导致其发生的直接原因是心脏早期发育异常。心脏的发育起源于心脏第一心区（First heart field，FHF）和第二心区（Second heart field，SHF）。SHF参与了心脏大部分细胞的形成，了解信号分子在心脏SHF中的调控机制非常重要。我们主要研究Notch信号通路是否调控以及如何调控第二生心区自我更新、增殖、分化和迁移。利用SHF特异性Isl1-Cre小鼠敲除Notch信号通路中的关键转录因子Rbpj，我们发现突变体中SHF来源的细胞不能形成正常的右心室，说明Rbpj对于SHF的发育是非常重要的。YAP1对于细胞的增殖具有重要的调控作用。我们在YAP1基因的启动子上游还发现了Rbpj的结合位点，说明Rbpj可能参与调控了YAP1的表达。综上所述，Notch信号通路可能通过YAP1参与调控了SHF的发育。该工作将帮助我们深入理解心脏发育的分子调控机制，为先天性心脏病的防治提供坚实的理论基础。