Genome-wide Analysis of Cardiac Development in Zebrafish

斑马鱼心脏发育的全基因组分析

• 批准号: 8127890
• 负责人: H. Joseph Yost
• 金额: $ 159.24万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127890
• 关键词: Bioinformatics; Biomedical Engineering; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cell Lineage; Child; Childhood; Chromatin; Chromatin Structure; Congenital Heart Defects; DNA Methylation; Data Set; Defect; Development; Epigenetic Process; Gene Expression; Genes; Genetic; Genomics; Goals; Human; Instruction; Laboratories; Literature; Messenger RNA; MicroRNAs; Modification; Molecular; Molecular Profiling; Morphogenesis; Organism; Output; Pattern; Pharmacological Treatment; Physiology; Publishing; Regulator Genes; Research; Research Infrastructure; Short Interspersed Nucleotide Elements; Small RNA; Transcriptional Activation; Zebrafish; gene repression; genetic manipulation; genetic selection; genome-wide; genome-wide analysis; insight; multidisciplinary; mutant; programs; research and development

DESCRIPTION (provided by applicant): We propose to build a multidisciplinary Zebrafish Cardiac Development Research Center with a collaborative group of zebrafish developmental biologists, zebrafish cardiac physiologists, and experts in chromatin structure, genome-wide gene network profiling, bioengineering and bioinformatics. We will investigate gene regulatory networks at distinct steps in development that control normal cardiac development at multiple molecular levels. Several diverse perturbations of cardiac development will serve as "inputs" to assess changes in cardiac development gene regulatory networks, including genetic mutants and morphants, embryological cell lineage manipulations and pharmacological treatments. The "outputs" will be analyses of chromatin structure that regulates transcriptional programs, epigenetic modifications including DNA methylation and chromatin marks that contribute to transcriptional activation (H3K4me3) or transcriptional repression (H3K9me3, and H3K27me3), genome-wide gene expression profiles (including mRNAs, microRNAs, SINE RNAs, other small RNAs) and transcriptional regulators involved in the patterning, morphogenesis and physiology of cardiomyocytes during development. Bioinformatics comparisons of normal and a large number of aberrant profiles within zebrafish will uncover molecular signatures of cardiac developmental defects. This multi-layered molecular profiling of cardiac development has not been performed in any organism. 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 molecular profiling program to rapidly obtain genome-wide molecular signatures. Our infrastructure will make these datasets readily accessible to the consortia for trans-species comparisons to uncover conserved molecular signatures relevant to human developmental heart defects. RELEVANCE (See instructions): Obtaining multi-layered molecular profiles of cardiac developmental defects will reveal the underlying causes of cardiac developmental defects, with the long term goal of applying these insights to treatment of children with heart defects.

描述（由申请人提供）： 我们建议建立一个多学科的斑马鱼心脏发育研究中心，由斑马鱼发育生物学家，斑马鱼心脏生理学家和染色质结构，全基因组基因网络分析，生物工程和生物信息学专家组成的合作小组。我们将研究基因调控网络在不同的发展阶段，控制正常的心脏发育在多个分子水平。心脏发育的几种不同扰动将作为“输入”，以评估心脏发育基因调控网络的变化，包括遗传突变体和变形，胚胎细胞谱系操作和药物治疗。“输出”将是对调节转录程序的染色质结构、包括DNA甲基化在内的表观遗传修饰和有助于转录激活（H3K4me3）或转录抑制的染色质标记的分析（H3K9me3和H3K27me3），全基因组基因表达谱在发育过程中，参与心肌细胞的模式化、形态发生和生理学的RNA（包括mRNA、microRNA、SINE RNA、其他小RNA）和转录调节因子。生物信息学比较正常和大量的斑马鱼异常配置文件将揭示心脏发育缺陷的分子特征。心脏发育的这种多层分子特征分析尚未在任何生物体中进行。随着新的候选基因或其他干扰（包括药理学或环境）在心脏发育联盟和儿科心脏基因组学联盟中出现，它们将被纳入这个多层分子谱分析计划，以快速获得全基因组分子特征。我们的基础设施将使这些数据集易于跨物种比较，以发现与人类发育性心脏缺陷相关的保守分子特征。相关性（参见说明）：获得心脏发育缺陷的多层分子谱将揭示心脏发育缺陷的根本原因，长期目标是将这些见解应用于治疗患有心脏缺陷的儿童。