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Atrial Fibrillation Post-GWAS: Mechanisms to Treatment

GWAS 后心房颤动：治疗机制

基本信息

批准号：
10646338
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
项目类别：
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/10646338
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 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 Phenotype Physiology Positioning Attribute 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 biobank candidate identification cardiac tissue engineering causal variant clinical application clinically actionable comorbidity dietary drug discovery drug testing egg gene interaction genome resource 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 pharmacologic prevent programs risk variant stressor synergism therapeutic evaluation transcriptome sequencing trimethylamine trimethyloxamine

项目摘要

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。