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Principal Investigator: Mina Kay Chung
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2024
Award: $2,784,815
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <21+ years old><4q25><AI system><Ablation><Address><Adult><Adult Human><Age><Amines><Animal Model><Animal Models and Related Studies><Apoplexy><Arrhythmia><Artificial Intelligence><Atrial><Atrial Fibrillation><Auricular Fibrillation><Back><Basic Research><Basic Science><Body Tissues><Brain Vascular Accident><Cardiac><Cardiac Arrhythmia><Cardiac Atrium><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Body><Cell Nucleus><Cell model><Cells><Cellular model><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cheese><Choline><Clinical><Collaborations><Computer Reasoning><Data><Data Bases><Databases><Diet><Dorsum><Drug Targeting><Drugs><Dysfunction><Electrophysiology><Electrophysiology (science)><Engineering><Environment><Fibrosis><Functional disorder><GI microbiome><GI microbiota><GWA study><GWAS><Gastrointestinal microbiota><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Targeting><Genes><Genetic><Genetic Risk><Genomics><Goals><Heart Arrhythmias><Heart Atrium><Heart Muscle Cells><Heart myocyte><History><Human><In Vitro><Incidence><Individual><Inflammasome><Inflammatory><Intermediary Metabolism><Intervention><Intervention Strategies><Investigators><Knowledge><LKB1><LKB1/STK11 Gene><Leanness><Left><Link><Machine Intelligence><Meat><Medication><Metabolic><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Mitochondria><Modern Man><Molecular><Murine><Mus><Muscle Cells><Myocytes><Neurophysiology / Electrophysiology><Nucleus><Obesity><Oxides><Pathway interactions><Patients><Pharmaceutical Preparations><Phenotype><Physiology><Physiopathology><Prevalence><Prevention><Preventive><Proteomics><Pulmonary veins><RNA Seq><RNA Sequences><RNA sequencing><RNAseq><Recording of previous events><Research><Research Personnel><Researchers><Risk><Risk Factors><Risk-associated variant><Role><STK11><STK11 gene><Single-Nucleus Sequencing><Stroke><Study models><Systems Biology><Testing><Therapeutic><Thinness><Tissue Model><Tissues><Transgenic Mice><Translating><Translations><Variant><Variation><adiposity><adulthood><ages><amine><atrium><biobank><biorepository><brain attack><candidate identification><cardiac tissue engineering><cardiomyocyte><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cerebral vascular accident><cerebrovascular accident><clinical applicability><clinical application><clinically actionable><co-morbid><co-morbidity><comorbidity><corpulence><data base><dietary><diets><digestive tract microbiome><drug detection><drug discovery><drug repositioning><drug repurposing><drug testing><drug/agent><egg><electrophysiological><engineered heart tissue><enteric microbial community><enteric microbiome><enteric microbiota><gastrointestinal microbial flora><gastrointestinal microbiome><gene interaction><gene locus><genetic locus><genome resource><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic data><genomic data resource><genomic data-set><genomic dataset><genomic location><genomic locus><genomic resource><genomic sequencing resource><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><histories><iPS><iPSC><iPSCs><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><inhibitor><insight><interventional strategy><intestinal biome><intestinal flora><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><liver kinase B1><metabolism measurement><metabolomics><metabonomics><mitochondrial><mitochondrial dysfunction><model of animal><mouse model><multidisciplinary><murine model><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><nutrition><pathophysiology><pathway><pharmacologic><prevent><preventing><programs><repurposing agent><repurposing medication><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><sNuc-Seq><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><stressor><stroked><strokes><synergism><therapeutic evaluation><therapeutic testing><transcriptome sequencing><transcriptomic sequencing><translation><whole genome association analysis><whole genome association studies><whole genome association study>