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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.