Atrial Fibrillation Post-GWAS: Mechanisms to Treatment

总体组件 项目/摘要 心房颤动（AF）是最常见的心律失常，日益困扰美国和世界 普遍性。AF发生率、持续性AF进展和AF并发症（包括卒中）由以下因素提供： 增加肥胖和年龄。目前的治疗受到风险和疗效的限制，如房颤， 研究进展，但在>10年内没有新的药物被批准用于AF。的标识 在全基因组关联研究（GWAS）中，>100个遗传位点易患AF风险，希望 遗传学将产生新的治疗靶点。然而，即使对于靠近PITX 2的染色体4 q25上的顶部基因座， 参与肺静脉形成的基因，房颤消融的靶点，将变体与房颤联系起来的机制 仍然难以捉摸迄今为止，遗传学研究结果未能产生临床可操作的结果。为了填补这些空白，我们 寻求超越GWAS的发现，以确定AF的直接基因组机制，并更好地理解 它们与环境、合并症或细胞应激源的相互作用。我们的长期目标是利用基因组 我们的总体P01主题是将AF转化为 基因发现走向床边，专注于基因机制，基因药物和相互作用 基因与新陈代谢和环境的关系。我们建立在强有力的初步数据基础上， 心房组织生物储存库和基因组数据资源，新的细胞和动物模型，以及互补的 我们的多学科团队拥有丰富的专业知识和强大的合作历史。我们的中心假设是， AF细胞和动物模型中的基因组机制发现将转化为人类疗法。我们 主题目标包括：1）确定致病基因和功能机制，目标是确定 AF的新治疗方法; 2）研究代谢和炎症机制， 基因组学研究在房颤病理生理学中很重要，以确定预防房颤的新治疗靶点 和治疗; 3）确定AF的候选新药，并开发体外和体内的管道 候选疗法的功能测试。项目1基因功能将确定致病基因，变异 和两个AF GWAS位点的潜在机制。项目2基因和代谢将研究 线粒体功能障碍与房颤发作和进展的关系。早期研究者项目基因和营养 建立在AF与由肠道微生物群产生的三甲胺N-氧化物（TMAO）的新关联的基础上， 前体物质，如鸡蛋、肉类和奶酪中的胆碱。项目4基因到Omics-Informed药物 确定预防AF进展的机制和可重复使用的药物。项目由4个核心支持 提供给药、工程化心脏组织和心房表型、电生理学和网络， 系统生物学分析支持，在AF中协同发现和翻译，并增加范围和 每个项目的影响。所有P01组件旨在将AF的基础研究与临床实用性联系起来，从而 将基因组数据和研究推向床边，以帮助我们的房颤患者。

OVERALL COMPONENT PROJECT/SUMMARY ABSTRACT Atrial fibrillation (AF), the most common cardiac arrhythmia, afflicts the U.S. and world with increasing prevalence. AF incidence, progression to persistent AF, and AF complications, including stroke, are fed by increasing obesity and age. Current therapies are limited by risks and limited efficacy, worse as AF progresses, but no new pharmacologic agents have been approved for AF in >10 years. With identification of >100 genetic loci that predispose to AF risk in genome-wide association studies (GWAS), the hope has been that genetics would yield novel therapeutic targets. However, even for the top locus on chr. 4q25 near PITX2, a gene involved in formation of pulmonary veins, the target of AF ablation, mechanisms linking variants to AF remain elusive. Genetic findings have so far failed to yield clinically actionable results. To fill these gaps, we seek to go beyond GWAS findings to identify direct genomic mechanisms underlying AF and better understand their interactions with environment, comorbidities or cell stressors. Our long-term goal is to use genomic findings to personalize preventive and therapeutic strategies for AF. Our overall P01 theme is to translate AF genetic discoveries towards the bedside, focusing on genes to mechanisms, genes to drugs, and interactions of genes with metabolism and environment. We build on strong preliminary data and coalesce unique human atrial tissue biorepository and genomic data resources, novel cell and animal models, and complementary expertise from our multidisciplinary team with a strong collaboration history. Our Central Hypothesis is that genomic mechanistic discoveries in AF cellular and animal models will translate to human therapies. Our thematic aims include: 1) Identify causal genes and functional mechanisms with a goal towards identification of new therapeutic approaches for AF; 2) Investigate metabolic and inflammatory mechanisms, implicated by genomics studies to be important in AF pathophysiology, to identify new therapeutic targets for AF prevention and treatment; and 3) Identify candidate novel drugs for AF and develop a pipeline for in vitro and in vivo functional testing of candidate therapies. Project 1 Genes to Function will determine causal genes, variants and mechanisms underlying two AF GWAS loci. Project 2 Genes and Metabolism will study the contribution of mitochondrial dysfunction to AF onset and progression. Early Stage Investigator Project Genes and Nutrition builds on novel associations of AF with trimethylamine N-oxide (TMAO), produced by gut microbiota from precursors such as choline found in eggs, meats and cheeses. Project 4 Genes to Omics-Informed Drugs will identify mechanisms and repurposable drugs to prevent AF progression. Projects are supported by 4 Cores providing administration, engineered heart tissue and atrial phenotyping, electrophysiology, and network and systems biology analytics support that synergize discovery and translation in AF and increase the scope and impact of each project. All P01 components aim to bridge basic research in AF towards clinical utility, thereby advancing genomic data and research towards the bedside to help our patients suffering from atrial fibrillation.