Atrial Fibrillation Post-GWAS: Mechanisms to Treatment

GWAS 后心房颤动：治疗机制

• 批准号: 10410643
• 负责人: Mina Kay Chung
• 金额: $ 284.16万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410643
• 关键词: 4q25; Ablation; Address; Adult; Age; Animal Model; Arrhythmia; Artificial Intelligence; Atrial Fibrillation; Back; Basic Science; Cardiac; Cardiac Myocytes; Cell Nucleus; Cell model; Cells; Cheese; Choline; Clinical; Collaborations; Data; Databases; Diet; Drug Interactions; Drug Targeting; Electrophysiology (science); Engineering; Environment; Fibrosis; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Risk; Genomics; Goals; Heart Atrium; Human; In Vitro; Incidence; Individual; Inflammasome; Inflammatory; Intervention; Knowledge; Left; Link; Meat; Metabolic; Metabolism; Methods; Mitochondria; Molecular; Mus; Muscle Cells; Obesity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Prevalence; Prevention; Preventive; Proteomics; Pulmonary veins; RNA Sequences; Recording of previous events; Research; Research Personnel; Risk; Risk Factors; Role; STK11 gene; Stroke; Study models; Systems Biology; Testing; Therapeutic; Thinness; Tissue Model; Tissues; Transgenic Mice; Translating; Translations; Variant; base; biobank; cardiac tissue engineering; causal variant; clinical application; clinically actionable; comorbidity; data resource; dietary; drug discovery; drug testing; egg; gene interaction; genetic variant; genome wide association study; genomic data; genomic locus; gut microbiome; gut microbiota; in vivo; induced pluripotent stem cell; inhibitor; insight; metabolomics; mitochondrial dysfunction; mouse model; multidisciplinary; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; nutrition; prevent; programs; risk variant; stressor; synergism; therapeutic evaluation; transcriptome sequencing; trimethylamine; trimethyloxamine

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.

总体组件 项目/摘要摘要 心房颤动（AF），最常见的心律不齐，使美国和世界增加 流行率。 AF发生率，持续性AF的进展以及包括中风在内的AF并发症由 增加肥胖和年龄。当前疗法受风险和有限效力的限制，随着AF 进展，但是在> 10年内，没有新的药理学剂获得AF的批准。与识别 >在全基因组关联研究（GWAS）中易于AF风险的100个遗传基因座（GWAS），希望是 该遗传学将产生新颖的治疗靶标。但是，即使是Chr上的顶部基因座。 4Q25靠近PITX2，A 涉及形成肺静脉的基因，即AF消融的靶标，将变体与AF联系起来的机制 保持难以捉摸。到目前为止，遗传发现未能产生临床可行的结果。为了填补这些空白，我们 寻求超越GWAS的发现，以识别AF基础的直接基因组机制并更好地理解 他们与环境，合并症或细胞压力源的相互作用。我们的长期目标是使用基因组 为AF的个性化预防和治疗策略的发现。我们的总体P01主题是翻译AF 对床边的遗传发现，专注于机制，药物基因和相互作用的基因 具有代谢和环境的基因。我们以强大的初步数据为基础，并结合独特的人类 心房组织生物座和基因组数据资源，新细胞和动物模型以及互补 我们的多学科团队的专业知识具有很强的合作历史。我们的中心假设是 AF细胞和动物模型中的基因组机械发现将转化为人类疗法。我们的 主题目的包括：1）确定因果基因和功能机制，其目标是确定 AF的新治疗方法； 2）研究代谢和炎症机制，与 基因组学研究在AF病理生理学中很重要，以确定预防AF的新治疗靶标 和治疗； 3）确定AF的候选新药物并开发体外和体内的管道 候选疗法的功能测试。项目1的功能基因将确定因果基因，变体 以及两个AF GWAS基因座的机制。项目2基因和代谢将研究 线粒体功能障碍对AF发作和进展。早期研究者项目基因和营养 建立在AF与三甲胺N-氧化物（TMAO）的新型关联建立，该氧化物由肠道微生物群生产 在鸡蛋，肉类和奶酪中发现的胆碱等前体。项目4的项目基因将 确定机制和可再利用的药物以防止AF进展。项目得到4个核心的支持 提供给药，工程心脏组织和心房表型，电生理学以及网络，以及 系统生物学分析支持在AF中协同发现和翻译并增加范围，并增加 每个项目的影响。所有P01组件旨在将AF的基础研究桥接到临床实用程序，从而 推进基因组数据和研究床边的研究，以帮助我们的心房纤颤的患者。