Functional Genomics of Atrial Fibrillation in Human Atria

人类心房心房颤动的功能基因组学

基本信息

批准号：
8851114
负责人：
John Barnard
金额：
$ 0.73万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-03 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851114
关键词：
4q25 Ablation Affect Aging Alleles American Atrial Fibrillation Bioinformatics Biological Biological Assay Cardiac Myocytes Cardiac Surgery procedures Cell Culture Techniques Cell Line Cells Cessation of life Chromosomes Clinical Complementary DNA Confounding Factors (Epidemiology)DNA Resequencing DNA Sequence Data Disease Distal Etiology Fibroblasts Finding by Cause Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genetic Variation Genomics Genotype Heart Heart Atrium Heart failure Human Incidence Intercistronic Region Interdisciplinary Study Lasers Left atrial structure Link Messenger RNA MicroRNAs Molecular Profiling Morphogenesis Muscle Cells Pathway interactions Patients Pattern Phenotype Predisposition Prevention Prevention therapy Protein Isoforms Proteins Pulmonary veins Quantitative Trait Loci RNA Sequences RNA Splicing Regulation Regulatory Element Reporter Genes Resources Risk Sampling Single Nucleotide Polymorphism Site Small Interfering RNA Stroke Technology Testing Tissues Transcript Transfection Validation Variant Weight base biobank candidate selection case control follow-up functional genomics gene function genetic variant genome wide association study genome-wide human embryonic stem cell human embryonic stem cell line innovation insight interest knock-down mRNA Stability next generation novel obesity risk transcriptome sequencing

4q25 Ablation Affect Aging Alleles American Atrial Fibrillation Bioinformatics Biological Biological Assay Cardiac Myocytes Cardiac Surgery procedures Cell Culture Techniques Cell Line Cells Cessation of life Chromosomes Clinical Complementary DNA Confounding Factors (Epidemiology)DNA Resequencing DNA Sequence Data Disease Distal Etiology Fibroblasts Finding by Cause Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genetic Variation Genomics Genotype Heart Heart Atrium Heart failure Human Incidence Intercistronic Region Interdisciplinary Study Lasers Left atrial structure Link Messenger RNA MicroRNAs Molecular Profiling Morphogenesis Muscle Cells Pathway interactions Patients Pattern Phenotype Predisposition Prevention Prevention therapy Protein Isoforms Proteins Pulmonary veins Quantitative Trait Loci RNA Sequences RNA Splicing Regulation Regulatory Element Reporter Genes Resources Risk Sampling Single Nucleotide Polymorphism Site Small Interfering RNA Stroke Technology Testing Tissues Transcript Transfection Validation Variant Weight base biobank candidate selection case control follow-up functional genomics gene function genetic variant genome wide association study genome-wide human embryonic stem cell human embryonic stem cell line innovation insight interest knock-down mRNA Stability next generation novel obesity risk transcriptome sequencing

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项目摘要

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) increases risk of heart failure, stroke and death, and AF has been found to have a significant heritable component. Genome wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with increased risk of AF. However, the causative variants, relevant genes and mechanisms by which they promote AF remain unclear. To enhance our understanding of the causative genes involved in heritable AF, we propose to evaluate the impact of SNPs identified in recent GWAS on the expression of messenger RNA, miRNA and related proteins in the target tissue of interest, human left atria, taken from a unique biorepository of over 1000 human atrial tissues from cardiac surgery patients. Specific aims are: 1) To determine how AF phenotypes alter the human atrial transcriptome, and 2) To identify and test candidate functional genetic variants that alter atrial transcript expression. Aim 1 studies will use state-of-the-art technology (RNA-seq, miRNA-seq) and bioinformatics to determine AF phenotype associations with gene transcripts, including lowly expressed transcripts and mRNA isoforms, and miRNAs, and co-regulated gene modules. We will test the functional effects of regulating selected genes using siRNA knockdown and cDNA transfection strategies in an atrial myocyte cell line, human ESC-derived atrial cells and in human atrial fibroblasts to determine whether altered expression of these genes affects downstream gene expression and selected biological pathways. Aim 2 studies will identify genetic variants associated with atrial gene expression by expression quantitative trait locus (eQTL), and allelic expression imbalance analyses. Candidate variants will be validated in reporter gene transfection studies. The proposed interdisciplinary studies are a logical and important follow up to recent GWAS that will provide novel, unbiased mechanistic insights into the impact of SNPs highly associated with AF on atrial RNA expression patterns. We expect our studies to identify functional links between AF-associated genetic loci and gene expression, and to identify SNPs, genes, and pathways that are causally related to the etiology and progression of AF and that may represent new targets for AF treatment and prevention.

描述（由申请人提供）：房颤（AF）增加了心力衰竭，中风和死亡的风险，并且已发现AF具有重要的遗传成分。基因组广泛的关联研究（GWAS）已经确定了与AF风险增加有关的许多单核苷酸多态性（SNP）。但是，它们促进AF的因果变异，相关基因和机制尚不清楚。为了增强我们对可遗传AF中涉及的致病基因的理解，我们建议评估GWAS中发现的SNP的影响，在感兴趣的目标组织中，人类左心房从心脏外科手术患者的1000多个人类手术组织中获得了人类左心房对梅尔纳，miRNA和相关蛋白的表达。具体目的是：1）确定AF表型如何改变人类心房转录组，以及2）识别和测试候选候选功能遗传变异，以改变心房转录表达。 AIM 1研究将使用最先进的技术（RNA-Seq，miRNA-Seq）和生物信息学来确定与基因转录本的AF表型关联，包括低表达的转录本和mRNA同工型，miRNA和miRNA，以及共同指导的基因模块。我们将使用siRNA敲低和cDNA转染策略在心房心肌细胞系，人ESC衍生的心房细胞以及人类心房成纤维细胞中测试调节所选基因的功能效应，以确定这些基因的表达是否改变了这些基因的表达是否影响下游基因表达和选定的生物学途径。 AIM 2研究将通过表达定量性状基因座（EQTL）和等位基因表达不平衡分析来鉴定与心房基因表达相关的遗传变异。候选变体将在报告基因转染研究中得到验证。拟议的跨学科研究是对最近的GWAS的逻辑和重要随访，它将为高度与AF相关的SNP的影响提供新颖的，无偏见的机理见解。我们希望我们的研究能够确定与AF相关的遗传基因座和基因表达之间的功能联系，并鉴定与AF的病因和进展有因果关系的SNP，基因和途径，并且可能代表AF治疗和预防的新目标。