Mechanisms of calcium-induced arrhythmias in arrhythmogenic right ventricular cardiomyopathy

致心律失常性右心室心肌病钙诱导心律失常的机制

基本信息

  • 批准号:
    10346038
  • 负责人:
  • 金额:
    $ 38.88万
  • 依托单位:
  • 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:
    2022-01-01 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY / ABSTRACT Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a complex inherited disorder of the heart produced by mutation in proteins of the desmosome, such as plakophilin-2 (PKP2). Cardiac arrhythmias, and potentially sudden death, often occur in ARVC patients during the early stages of the disease, a “concealed phase” that presents before the onset of structural cardiomyopathy. The molecular and cellular mechanisms of these arrhythmic events remain unclear, hindering the search for effective strategies to treat patients. My long-term goal is to delineate the mechanisms of arrhythmia in ARVC and to identify potential drug targets to prevent sudden cardiac death. Mice with tamoxifen (TAM)-induced ablation of PKP2 (PKP2cKO) develop a phenotype evocative of human ARVC: a concealed stage with high incidence of arrhythmia but without structural remodeling at 14 days, cardiomyopathy of right ventricle dominance at 21 days, and biventricular cardiomyopathy, heart failure and death at ~42 days post-TAM. We reported that PKP2cKO hearts show significant dysregulation of Ca2+ handling at different stages of disease progression but, most remarkably, during the concealed stage of the disease. This proposal aims to elucidate the mechanisms underlying cardiac arrhythmia in PKP2-deficient hearts focusing on the microdomain where Ca2+ regulation takes place. I hypothesize that dysfunction of the cardiac ryanodine receptor (RyR2), a major intracellular Ca2+ release channel, and the ensuing Ca2+ mishandling are critical triggers of cardiac arrhythmia in the PKP2cKO mouse and, hence, in ARVC. These aims will test my hypothesis: 1) Determine the role of protein kinase C (PKC) phosphorylation in the regulation of RyR2 channel function and calcium homeostasis. Preliminary data suggest that RyR2 is undergoing phosphorylation in PKP2cKO hearts at Thr2810. This previously uncharacterized site is a predicted PKC substrate. I hypothesize that PKC phosphorylation of RyR2 at Thr2810 regulates channel function and contributes to arrhythmogenic Ca2+ release in the diseased heart. 2) Define the contribution of RyR2 dysfunction in the onset and progression of heart disease in PKP2cKO mice. Preliminary data suggest that RyR2 phosphorylation at Thr2810 and Ser2030 is increased in ARVC. I hypothesize that inhibition of RyR2 phosphorylation at these sites prevents arrhythmia and sudden death in PKP2cKO mice. 3) Test the efficacy of RyR2 modulators for the prevention of arrhythmia in PKP2-deficient hearts. I hypothesize that pharmacological modulation of RyR2 is beneficial to prevent arrhythmia in PKP2cKO mice and hearts. The completion of these aims will provide significant insight into the regulation of RyR2 function in a model of PKP2cKO deficiency and hence shed light on the mechanisms underlying ARVC. I anticipate these results will advance the status of RyR2 as a potential therapeutic target to reduce the risk of arrhythmias and increase life-expectancy of patients with ARVC.
项目摘要/摘要

项目成果

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Francisco J Alvarado其他文献

Francisco J Alvarado的其他文献

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{{ truncateString('Francisco J Alvarado', 18)}}的其他基金

2023 Muscle: Excitation-Contraction Coupling Gordon Research Conference and Gordon Research Seminar
2023肌肉:兴奋-收缩耦合戈登研究会议暨戈登研究研讨会
  • 批准号:
    10606049
  • 财政年份:
    2023
  • 资助金额:
    $ 38.88万
  • 项目类别:
Partial and Controlled Depletion of SR Calcium by RyR Agonists Prevents Calcium-dependent Arrhythmias
RyR 激动剂部分且受控地消耗 SR 钙可预防钙依赖性心律失常
  • 批准号:
    10577630
  • 财政年份:
    2023
  • 资助金额:
    $ 38.88万
  • 项目类别:
Mechanisms of calcium-induced arrhythmias in arrhythmogenic right ventricular cardiomyopathy
致心律失常性右室心肌病钙诱导心律失常的机制
  • 批准号:
    10539305
  • 财政年份:
    2022
  • 资助金额:
    $ 38.88万
  • 项目类别:

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