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Non-junctional roles of desmosome proteins in the pathogenesis of arrhythmogenic cardiomyopathy

桥粒蛋白在致心律失常性心肌病发病机制中的非连接作用

基本信息

批准号：
10705361
负责人：
HUEI-SHENG Vincent CHEN
金额：
$ 50.16万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2022-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705361
关键词：
1-Phosphatidylinositol 3-Kinase Adult Affect Amino Acids Angiotensin II Receptor Anti-Inflammatory Agents Apoptosis Arrhythmia Arrhythmogenic Right Ventricular Dysplasia Binding Binding Sites CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiovascular Diseases Cause of Death Chromatin Clinical Cloning Complex Desmosomes Disease model Down-Regulation Dystrophin Elements Gene Mutation Genes Genetic Genetic Transcription Heart Heart Diseases Histone Deacetylase Inhibitor Human Hyperactivity Hypertension In Vitro Indomethacin Infiltration Insulin Insulin Receptor Insulin Resistance Knock-out Lead Luciferases Mediating Membrane Messenger RNA Metabolic Metabolism Methods MicroRNAs Modeling Mutation Myocardial dysfunction Nature PPAR alpha PPAR gamma Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Point Mutation Proline Promoter Regions Property Proteins Protocols documentation Right ventricular structure Role Sampling Scheme Signal Pathway Signal Transduction Site Site-Directed Mutagenesis Sodium Channel Somatic Cell Steroids Sudden Death System Testing Therapeutic Therapeutic Agents Therapeutic Studies Time Tissues Toxic effect Trichostatin A Tryptophan Tyrosine analog arrhythmogenic cardiomyopathy base beta catenin caveolin-2 caveolin-3 clinical efficacy clinically relevant fatty acid oxidation human model in vitro Model in vivo Model induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes inherited cardiomyopathy inhibitor innovation insight insulin signaling lipid biosynthesis mouse model mutant new therapeutic target novel novel therapeutic intervention novel therapeutics nucleocytoplasmic transport patch clamp plakoglobin plakophilin 2 promoter rosiglitazone side effect transcription factor valsartan vector young adult

项目摘要

PROJECT SUMMARY Cardiovascular diseases remain the major cause of death in the US. Recent advances in reprogramming somatic cells from cardiac patients into induced pluripotent stem cells (iPSCs) enables in vitro modeling of human cardiac diseases for pathogenic studies and therapeutic screens. Traditionally, weakened desmosome junctions are considered the main pathogenic mechanism for Arrhythmogenic Cardiomyopathy (AC), caused by mutations in five desmosome component proteins. Pathological hallmarks of AC are progressive fibro-fatty replacement of cardiomyocytes (CMs) with increased CM apoptosis primarily in the RV, leading to sudden death in the young. We have established a novel method to induce adult-like, fatty acid oxidation-dominant metabolism of primitive CMs derived from iPSCs (iPSC-CMs) and established the first metabolic maturation- based in vitro cardiac disease model for elucidation of novel pathogenic insights for human AC (Nature, 2013). We showed that abnormal PPARγ activation after normal PPARα-mediated metabolic maturation in AC CMs resulted in exaggerated lipogenesis, apoptosis, sodium channel deficits and defective Ca2+ handling in CMs with desmosome mutations, recapitulating the pathological signatures of AC hearts. Using our AC model and samples from pathological human AC hearts, we show here that plakoglobin is a key component of Insulin-p85 metabolic signaling complex. Desmosome mutations lead to faster plakoglobin degradation, reduce PI3K/Akt activation, and hyperactivate GSK3β, which downregulate a microRNA (miR) cluster leading to subsequent abnormal PPARγ activation and CM apoptosis. Importantly, we used genetic and cellular methods to confirm the clinically relevance of our pathogenic pathways in human AC hearts and in mouse models of AC. We propose here to further elucidate the dysregulated and non-junctional signaling networks caused by plakoglobin deficits, to study how plakophilin-2 deficits deregulate additional signaling pathways, and to find clinically safe therapeutic agents for treating AC using both in vitro iPSC-CM based models and mouse models of AC.

项目总结