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: 7936087
• 负责人: H. Joseph Yost
• 金额: $ 157.63万
• 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/7936087
• 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; 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 association study; 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）： 我们建议与斑马鱼发育生物学家，斑马鱼心脏生理学家以及染色体质结构，全基因组全基因网络概况，生物学和生物学和生物信息学的专家建立一个多学科的斑马鱼心脏发展研究中心。我们将在开发的不同步骤中研究基因调节网络，以控制多个分子水平的正常心脏发育。心脏发展的几种不同扰动将作为评估心脏发展基因调节网络变化的“投入”，包括遗传突变体和形态，胚胎细胞谱系操纵和药理学治疗。 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)以及参与发育过程中心肌细胞的图案，形态发生和生理学的转录调节剂。斑马鱼内正常和大量异常特征的生物信息学比较将发现心脏发育缺陷的分子特征。这种心脏发育的多层分子分析尚未在任何生物体中进行。由于新候选基因或其他扰动（包括药理学或环境）在心脏发育联盟和小儿心脏基因组学联盟内出现，因此它们将被纳入该多层分子概况计划中，以快速获得全基因组分子签名。我们的基础架构将使这些数据集可容易地访问联盟，以进行跨物种比较，以发现与人类发育性心脏缺陷有关的保守分子特征。相关性（请参阅说明）：获得心脏发育缺陷的多层分子曲线将揭示心脏发育缺陷的根本原因，其长期目标是将这些见解应用于心脏缺陷的儿童治疗。