Atrial Fibrillation Post-GWAS: Mechanisms to Treatment

GWAS 后心房颤动：治疗机制

基本信息

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
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/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

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.

整体组成项目/摘要摘要心房颤动 (AF) 是最常见的心律失常，越来越多地困扰着美国和世界各地。流行率。 AF 发生率、进展为持续性 AF 以及 AF 并发症（包括中风）由肥胖和年龄增加。目前的治疗方法受到风险和疗效的限制，更糟糕的是房颤进展，但超过 10 年没有新的药物被批准用于 AF。具有身份识别在全基因组关联研究 (GWAS) 中，超过 100 个易患 AF 风险的基因位点，希望已被证实遗传学将产生新的治疗靶点。然而，即使对于 chr 上的顶部基因座。 PITX2 附近的 4q25，a 参与肺静脉形成的基因、房颤消融的目标、变异与房颤相关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上可行的结果。为了填补这些空白，我们寻求超越 GWAS 研究结果来确定 AF 背后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学研究结果可个性化制定 AF 的预防和治疗策略。我们P01的整体主题是翻译AF 床边的基因发现，重点关注基因到机制、基因到药物以及相互作用基因与新陈代谢和环境的关系。我们以强大的初步数据为基础，融合独特的人类心房组织生物储存库和基因组数据资源、新颖的细胞和动物模型以及补充来自我们具有悠久合作历史的多学科团队的专业知识。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。我们的主题目标包括： 1) 确定因果基因和功能机制，目标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 AF 病理生理学中很重要，可以确定预防 AF 的新治疗靶点和治疗； 3) 确定治疗 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 基因功能将确定因果基因、变异以及两个 AF GWAS 位点的潜在机制。项目 2 基因与代谢将研究线粒体功能障碍导致房颤的发生和进展。早期研究员项目基因与营养建立在 AF 与三甲胺 N-氧化物 (TMAO) 的新关联之上，TMAO 是由肠道微生物群产生的鸡蛋、肉类和奶酪中发现的胆碱等前体。项目 4 基因组学药物将确定预防 AF 进展的机制和可重新利用的药物。项目由 4 核支持提供管理、工程心脏组织和心房表型、电生理学和网络和系统生物学分析支持协同 AF 的发现和翻译，并扩大范围和每个项目的影响。所有 P01 组件均旨在将 AF 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临床，以帮助患有房颤的患者。