Genome-Wide Analysis of Cardiac Development in Zebrafish

 描述(申请人提供)：犹他州心血管发育(CvDC)研究中心是一个由斑马鱼发育生物学家、斑马鱼心脏生理学家以及染色质结构、全基因组基因网络图谱、蛋白质组学和生物信息学专家组成的合作团队。我们的目标是发现先天性心脏病(CHD)的病因。我们实现这一目标的战略计划是：(1)利用斑马鱼生成大型多方面全基因组数据库(RNA-SEQ、亚硫酸氢盐DNA-SEQ、CHIP-SEQ)，以发现基因调控网络(GRN)，这些GRN在正常发育的精确时间点运行，更重要的是，在导致心脏发育异常、引发CHD的多种遗传途径扰动中运行；(2)了解这些GRN运行的细胞谱系，以及这些GRN在CHD中的相互依赖；(3)合作应用这些方法来测试来自儿科心脏基因组学联合会(PCGC)的人类遗传学研究以及CvDC其他中心的细胞培养和小鼠模型研究的候选基因。我们热切期待这个斑马鱼模型系统的投入将通过联合体中的互动继续进化；(4)继续开发新的生物信息学工具 和技术创新，以发现改变冠心病GRN的突变和机制，最重要的是(5)通过开发和加强基于网络的工具，包括CvDC数据共享中心，继续在B2B财团和整个研究界共享这些资源。当心脏发育联盟和儿科心脏基因组联盟出现新的候选基因或其他干扰(包括药物或环境)时，它们将被整合到斑马鱼的这个多层基因组范围的分子图谱计划中。然后，我们的GRN分析可以加强对导致人类冠心病的遗传途径的搜索。我们的基础设施将使这些数据集随时可供财团进行跨物种比较，以揭示与人类先天性心脏病相关的保守分子特征。

 DESCRIPTION (provided by applicant): The Utah Cardiovascular Development (CvDC) Research Center is a collaborative team of zebrafish developmental biologists, zebrafish cardiac physiologists, and experts in chromatin structure, genome-wide gene network profiling, proteomics and bioinformatics. Our goal is to discover the etiologies of Congenital Heart Disease (CHD). Our strategic plan to reach this goal is to (1) utilize zebrafish to generate large multifaceted genome-wide databases (RNA-seq, bisulfite DNA-seq, ChIP-seq) to discover the Gene Regulatory Networks (GRNs) that operate at precise time points in normal development and, importantly, in a multitude of genetic pathway perturbations that result in aberrant cardiac development, giving rise to CHD; (2) understand the cell lineages in which these GRNs operate, and the interdependence of these GRNs in CHDs; (3) collaboratively apply these approaches to test candidate genes that arise from human genetics studies in the Pediatric Cardiac Genomics Consortium (PCGC) and from studies in cell culture and mouse models in other centers of the CvDC. We enthusiastically expect that the inputs into this zebrafish model system will continue to evolve through interactions in the consortia; (4) continue to develop novel bioinformatics tools and technological innovations for the discovery of mutations and mechanisms that alter GRNs in CHD, and most importantly (5) continue to share these resources across the B2B consortia and with the research community at large, by developing and enhancing web-based tools, including the CvDC Data Sharing Hub. As new candidate genes or other perturbations (including pharmacological or environmental) arise within the Cardiac Development Consortium and Pediatric Cardiac Genomics Consortium, they will be incorporated into this multi-layered genome-wide molecular profiling program in zebrafish. Our GRN analysis can then enhance the search for genetic pathways that cause CHD in humans. Our infrastructure will make these datasets readily accessible to the consortia for trans-species comparisons to uncover conserved molecular signatures relevant to human Congenital Heart Disease.