Fine-scale Spatiotemporal Mapping of Cellular Regulatory Networks Directing Heart Development

项目摘要 先天性心脏病是新生儿最常见的先天性异常，占三分之一 所有重大先天性异常的原因尽管最近的先天性心脏病遗传研究强调， 心脏转录和染色质调节因子在心脏发育过程中的关键作用，我们对 这些发育调节因子如何相互作用，形成动态的基因调控网络， 心脏发育仍有待充分阐明。因此，我们建议定义和测定心血管 发育调节因子及其基因调控网络，指导了大量的 心血管细胞类型创造哺乳动物心脏。为了实现这一目标，多学科实验 和计算系统生物学的方法将实施：（1）阐明基因调控网络 建立发育中哺乳动物心脏的心源性细胞等级，（2）研究 小鼠胚胎发生和心脏期间心源性细胞层次的时空组织 形态发生和（3）功能检查不同的心血管发育来源如何产生特定的 心血管谱系有助于心脏的发育。

Project Summary Congenital Heart Disease is the most common congenital anomaly in newborn babies, accounting for one third of all major congenital anomalies. Despite recent congenital heart disease genetic studies highlighting the critical role of cardiac transcriptional and chromatin regulators during heart development, our understanding of how these developmental regulators interact to create the dynamic gene regulatory networks that mediate heart development remains to be fully elucidated. Thus, we propose to define and assay the cardiovascular developmental regulators and their gene regulatory networks that direct the development of the vast array of cardiovascular cell types creating the mammalian heart. To achieve this goal, a multi-disciplinary experimental and computational systems biology approach will be implemented to: (1) elucidate gene regulatory networks that establish the cardiogenic cellular hierarchy of the developing mammalian heart, (2) investigate the spatiotemporal organization of the cardiogenic cellular hierarchy during mouse embryogenesis and heart morphogenesis and (3) functionally examine how distinct cardiovascular developmental sources create specific cardiovascular lineages contributing to the developing heart.