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.

整体组件 项目/摘要摘要 房颤(房颤)是最常见的心律失常，日益严重地困扰着美国和世界。 流行率。房颤的发生率、进展为持续性房颤以及包括中风在内的房颤并发症是由 不断增加的肥胖和年龄。目前的治疗方法受到风险和疗效的限制，更糟糕的是房颤 取得了进展，但10年来没有新的药理药物被批准用于房颤。带有身份标识的 在全基因组关联研究中，100个易患房颤风险的遗传基因座被寄予希望 这种遗传学将产生新的治疗靶点。然而，即使是CHR上的顶级基因座。4q25靠近PITX2，a 参与肺静脉形成的基因，房颤消融的靶点，变异与房颤的联系机制 仍然难以捉摸。到目前为止，遗传学发现还没有产生临床上可操作的结果。为了填补这些空白，我们 寻求超越GWAS的发现，以确定房颤的直接基因组机制，并更好地理解 它们与环境、共病或细胞应激源的相互作用。我们的长期目标是利用基因组 使房颤的预防和治疗策略个性化的研究结果。我们P01的总体主题是翻译AF 床边的基因发现，重点是基因到机制，基因到药物，以及相互作用 基因与新陈代谢和环境的关系。我们建立在强大的初步数据基础上，并将独特的人类 心房组织生物信息库和基因组数据资源，新的细胞和动物模型，以及互补 来自我们的多学科团队的专业知识，以及强大的协作历史。我们的中心假设是 房颤细胞和动物模型中的基因组机制发现将转化为人类疗法。我们的 主题目标包括：1)确定致病基因和作用机制，目的是确定 房颤的新治疗方法；2)研究代谢和炎症机制，涉及 基因组学研究在房颤病理生理学中的重要作用，为房颤预防寻找新的治疗靶点 和治疗；3)寻找治疗房颤的候选新药，并开发体外和体内治疗流水线 候选疗法的功能测试。项目1的功能基因将决定因果基因、变种 以及两个房颤基因座的遗传机制。项目2基因和新陈代谢将研究 线粒体功能障碍与房颤的发生和发展。早期研究人员项目基因和营养 建立在房颤与三甲胺N-氧化物(TMAO)的新关联基础上，由肠道微生物群从 鸡蛋、肉类和奶酪中含有的前体，如胆碱。将4个基因投射到Omics--知情药物 确定预防房颤进展的机制和可重复使用的药物。项目由4核支持 提供给药、工程心脏组织和心房表型、电生理学和网络以及 系统生物学分析支持在房颤中协同发现和翻译，并增加范围和 每个项目的影响。所有P01成分都旨在将房颤的基础研究与临床应用联系起来，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。