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The molecular mechanisms underlying arrhythmogenic right ventricular dysplasia/cardiomyopathy

致心律失常性右心室发育不良/心肌病的分子机制

基本信息

批准号：
9036430
负责人：
Farah Sheikh
金额：
$ 38.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9036430
关键词：
Accounting Adult Affect Arrhythmogenic Right Ventricular Dysplasia Autophagocytosis Autophagosome Behavior Binding Biochemical Biological Models Biology Cardiac Cardiac Myocytes Cardiomyopathies Cells Clinical Complex Congenital cardiomyopathy Connexins DNA Sequence Alteration Data Defect Desmosomes Diagnosis Disease Electrophysiology (science)Employee Strikes Event Exhibits Family Funding Generations Genes Genetic Genetic Models Goals Grant Health Heart Heart Abnormalities Heart Diseases Human In Vitro Intercellular Junctions Knockout Mice Link Lysosomes Mediating Microscopy Modeling Molecular Molecular Genetics Morphology Mus Mutation Myocardium Patients Physiological Physiology Protein Family Proteins Role SNAP receptor Structure Sudden Death Testing Validation Yeasts base desmoplakin effective therapy human tissue in vivo induced pluripotent stem cell insight knock-down lentiviral-mediated loss of function member mouse model novel overexpression protein degradation protein function small hairpin RNA soluble NSF attachment protein sudden cardiac death targeted treatment tool yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): This is an application for a competitive renewal of our grant R01 HL095780-01. We were originally funded to investigate mechanisms underlying the role of the known central desmosomal component, desmoplakin, in the clinical and cellular features associated with the genetic-based heart disease, arrhythmogenic right ventricular cardiomyopathy (ARVC) that causes sudden death in the young, by generating and characterizing novel desmoplakin deficient model systems. For this application, we uncovered synaptosomal associated protein 29 (SNAP29) as a novel desmoplakin associated protein in the adult human heart in a yeast-two hybrid screen that we show has relevance to ARVC, by leveraging our novel genetic mouse and human cardiac models of ARVC. Although the role of SNAP29 is unknown in the heart, we show that SNAP29 co-localizes to cardiac muscle desmosomal cell-cell junctions in the adult mouse and human heart as well as human induced pluripotent stem cell derived cardiac cells (hiPSC). Furthermore, SNAP29 localization and/or levels at desmosomal junctions are lost in hearts from our mouse model of ARVC and ARVC hiPSC-derived cardiac cells that exhibit striking desmosomal defects and arrhythmogenic behavior. Generation of novel SNAP29 deficient mouse models (global and cardiomyocyte-specific) revealed striking cardiac defects including (i) autophagic defects at the cardiac muscle cell junction (accumulation of autophagic/lysosomal markers and structures at the cell junction) that specifically impacted desmosomal protein levels and (ii) cardiac morphology defects. Data from our mouse model of ARVC provides validation to this mechanism as we reveal that their hearts exhibit similar defects in autophagic control at the cardiac muscle cell junction. We hypothesize that SNAP29 regulates desmosomal protein levels and function in cardiac muscle by controlling desmosomal turnover via autophagy-mediated mechanisms and its loss will trigger loss of desmosomal protein levels as well as function and ultimately cause ARVC. We aim to determine: (i) the functional role of SNAP29 in the heart by characterizing SNAP29 loss of function mouse models, (ii) the relevance of SNAP29-DSP interaction in human ARVC and cardiomyocytes by expressing human ARVC mutations and using hiPSCs as a tool, and (iii) the SNAP29-dependent events in autophagy that control desmosomal levels/turnover, by analyzing defects in cardiac autophagy (induction and flux) and relevant desmosome targets using SNAP29 loss of function models and overexpression of SNAP29 in an in vitro ARVC model.