Targeting Protein Trafficking in Arrhythmogenic Cardiomyopathy

致心律失常性心肌病中的靶向蛋白质运输

• 批准号: 10301665
• 负责人: Joseph A. Palatinus
• 金额: $ 17.93万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301665
• 关键词: Actins; Address; Affect; Age; Animal Model; Arrhythmia; Biology; Birth; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cell model; Cessation of life; Cicatrix; Co-Immunoprecipitations; Confocal Microscopy; Connexin 43; Connexins; Coronary; Coupling; Data; Defect; Defibrillators; Desmosomes; Devices; Disease; Disease model; Doctor of Philosophy; Echocardiography; Educational workshop; Electron Microscopy; Gap Junctions; Goals; Heart; Heart Diseases; Hela Cells; Institutes; Intercalated disc; International; Ion Channel; Ischemia; Knock-out; Knowledge; Laboratories; Ligation; Link; Location; Mediating; Mentors; Metabolic; Mitochondria; Modeling; Molecular; Monitor; Mus; Mutant Strains Mice; Mutation; Myocardial; Myocardial dysfunction; Names; Normal Statistical Distribution; Outcome; Oxygen; Pathologic; Patients; Phenotype; Physical activity; Physicians; Prevention; Protein Isoforms; Proteins; Recovery; Regulation; Reproducibility; Research; Research Personnel; Research Training; Resolution; Robin bird; Role; Scientist; Signal Transduction; Structure; Sudden Death; Targeted Research; Techniques; Telemetry; Testing; Training Programs; Transfection; Translating; Translational Research; United States; United States National Institutes of Health; Universities; Utah; Virus; Vocational Guidance; Work; arrhythmogenic cardiomyopathy; base; cardioprotection; career development; desmoglein 2; effective therapy; experience; implantation; improved; in vivo; insight; knock-down; medical schools; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; preservation; prevent; professor; protein transport; sudden cardiac death; symposium; targeted treatment; trafficking

ABSTRACT This proposal is to support the career development of Joseph Palatinus, MD, PhD, to become an independent physician scientist with a focus on basic/translational research by targeting protein trafficking as a means to prevent and treat arrhythmias and sudden cardiac death (SCD). The PI will have as a primary mentor Professor Robin Shaw, MD PhD, who is world renowned expert in protein trafficking and cardiomyocyte biology. The comprehensive training program is composed of laboratory-based research, coursework, workshops, grantsmanship seminars, scientific conferences (local and international), and career guidance by a mentoring committee. The committee includes the mentors and leverages the combined experience and technical knowledge of 5 leading independent cardiovascular investigators at the Eccles Cardiovascular Research and Training Institute at the University of Utah as well as Dr. Jeffery Saffitz at Harvard Medical School, a world expert on Arrhythmogenic cardiomyopathy. The research proposed will apply the alternatively translated isoform of Connexin 43 (Cx43), dubbed GJA1-20k (and an established actin stabilizing protein), to the Desmoglein 2 (DSG2) mutant model of ACM. Preliminary data has demonstrated disrupted actin organization in both cellular and animal models of a DSG2 mutation which, in the heart is associated with a loss of gap junction trafficking to the intercalated disk and downstream cardiac dysfunction. It is hypothesized that GJA1-20k will lead to recovery of gap junction localization, suppression of arrhythmias and prevention of SCD in the DSG2 mutant model of ACM by directly interacting with and stabilizing cellular actin. Two specific aims are proposed: 1) Is actin dysregulation responsible for the trafficking defects observed in the DSG2 mutant model? And 2) Does GJA1- 20k rescue the cardiomyopathic and arrhythmogenic phenotype of ACM and prevent SCD? High resolution confocal microscopy, proximity ligation immunolabeling, electron microscopy, co- immunoprecipitation, echocardiography, and in vivo telemetry monitoring are some of the advanced techniques which will be used to develop a mechanistic understanding of actin dependent trafficking mediated by GJA1-20k. The results from this study are expected to develop a novel paradigm to treat and prevent arrhythmogenic SCD by targeting protein trafficking.

摘要