A Community Zebrafish Resource for Modeling GWAS Biology

用于 GWAS 生物学建模的社区斑马鱼资源

基本信息

批准号：
9763679
负责人：
Wolfram Goessling
金额：
$ 77.09万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763679
关键词：
ATAC-seq Affect Algorithm Design Alleles Animal Model Archives Award Bioinformatics Biological Biological Assay Biological Models Biology Blood CRISPR/Cas technology Candidate Disease Gene Catalogs Cell Lineage ChIP-seq Code Communities Companions Complement Complex Databases Development Disease Disease model Epigenetic Process Etiology Evaluation Fishes Gene Expression Genes Genetic Genetic Models Genetic Variation Genomic Segment Genomics Guide RNA Heart Human Human Biology Human Genome Individual Liver Location Maintenance Maps Medical Modeling Molecular Mosaicism Mus Nucleic Acid Regulatory Sequences Organ Pathway interactions Pharmaceutical Preparations Phenotype Production Reagent Regulator Genes Regulatory Element Research Personnel Resources Role Signal Transduction Study models Surveys System Technology Testing Tissues Transgenic Organisms Translations Untranslated RNA Variant Whole Organism Work Zebrafish algorithmic methodologies assay development base cell type disease mechanisms study disease phenotype drug discovery experience gain of function gene function gene interaction genetic variant genome editing genome wide association study genomic variation human disease in vivo in vivo Model innovation insight mutant novel novel strategies response trait transcriptome sequencing web site

项目摘要

PROJECT SUMMARY: Our proposal “Community Zebrafish Resource for Modeling GWAS Biology” applies novel approaches, algorithms and methods developed within our consortium for functional analysis of human GWAS hits using the zebrafish model system. Our consortium has accumulated broad experience in zebrafish genetics, genome editing, bioinformatics, functional assay development, and human disease modeling as well as innovative mechanistic studies to elucidate individual gene function. During the previous cycle of the award, we established efficient high-content platforms for the functional analysis of coding sequence variation in zebrafish to complement GWAS projects across a variety of complex human traits, and provided pathway entry points and genetic models for understanding disease. In this renewal application, we extend our functional exploration of single and/or multiple GWAS loci and their roles in biological networks underlying human medical traits to include prevalent non-coding variation and drug responses through the following Specific Aims: Aim 1-Functionally analyze loci from multiple GWAS studies on blood, liver, heart and vessel traits, optimizing assay development and gene editing using CRISPR-Cas9 technology in zebrafish. a) Using validated assays we will examine the function of multiple coding genes in GWAS loci and generate genetic models in the zebrafish using CRISPR-Cas9 technology. b) Accelerate in vivo gene function evaluation by optimization of genome editing in zebrafish using the CRISPR-Cas9 technology. Aim 2-Survey landscapes of genomic regulatory regions in different cell lineages in zebrafish and use the information to support better mapping and functional evaluation of regulatory variants from GWAS loci. a) Using ATAC-seq, ChIP-seq, Methyl-seq, and companion RNA-seq analyses we will establish a comprehensive database of conserved (orthologous) regulatory regions in different cell lineages and organs of both zebrafish and human. We will define regulatory regions in different cell types at different developmental stages which are important for cell lineage differentiation, maintenance and function in zebrafish. b) We will map regulatory effects from GWAS loci to conserved zebrafish regulatory regions and test individual and/or multiple regulatory effects for their roles in specific GWAS traits using genome editing technology and validated functional assays in zebrafish. c) Categorize conserved GWAS loci based on function and catalog genome editing reagents for disease modeling and mechanistic studies and drug discovery.

项目概要：我们的提案“用于 GWAS 生物学建模的社区斑马鱼资源”采用了新颖的方法，我们联盟开发的算法和方法，用于使用以下方法对人类 GWAS 命中进行功能分析我们的联盟在斑马鱼遗传学、基因组方面积累了丰富的经验。编辑、生物信息学、功能分析开发、人类疾病建模以及创新在上一个奖项周期中，我们进行了阐明个体基因功能的机制研究。建立了高效的高内涵平台，用于斑马鱼编码序列变异的功能分析补充涵盖各种复杂人类特征的 GWAS 项目，并提供路径切入点和理解疾病的遗传模型在这个更新应用中，我们扩展了我们的功能探索。单个和/或多个 GWAS 位点及其在人类医学特征的生物网络中的作用通过以下具体目标包括普遍的非编码变异和药物反应：目标 1 - 对血液、肝脏、心脏和血管特征的多项 GWAS 研究的基因座进行功能分析，优化使用 CRISPR-Cas9 技术在斑马鱼中进行检测开发和基因编辑。 a) 使用经过验证的检测方法，我们将检查 GWAS 基因座中多个编码基因的功能，使用 CRISPR-Cas9 技术在斑马鱼中生成遗传模型。 b) 使用以下方法优化斑马鱼基因组编辑，加速体内基因功能评估 CRISPR-Cas9技术。目标 2-调查斑马鱼不同细胞谱系的基因组调控区域的景观并使用信息以支持对 GWAS 位点的调控变异进行更好的定位和功能评估。 a) 使用 ATAC-seq、ChIP-seq、Mmethyl-seq 和同伴 RNA-seq 分析，我们将建立不同细胞谱系和器官中保守（直系同源）调控区域的综合数据库我们将定义斑马鱼和人类不同细胞类型的调控区域。对斑马鱼细胞谱系分化、维持和功能很重要的阶段。 b) 我们将绘制从 GWAS 位点到保守斑马鱼调控区域的调控效应并进行测试使用基因组编辑对其在特定 GWAS 性状中的作用进行个体和/或多重调节效应斑马鱼技术和经过验证的功能测定。 c) 根据功能对保守的 GWAS 位点进行分类，并为基因组编辑试剂编目疾病建模和机制研究以及药物发现。