Arrhythmogenic Cardiomyopathy is an Inflammatory Disease

致心律失常性心肌病是一种炎症性疾病

基本信息

批准号：
10132387
负责人：
JEFFREY E SAFFITZ
金额：
$ 50.34万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132387
关键词：
Adverse event Agonist Alleles Anti-Inflammatory Agents Apoptosis Arrhythmia Automobile Driving Cardiac Cardiac Myocytes Cells Chronic Clinical Clinical Trials Dangerousness Data Development Disease Disease Progression Event Exercise FDA approved Functional disorder Future Goals Heart Immune Immune response In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Infiltrate Injury Innate Immune Response Interleukin-1 beta Malignant Neoplasms Mediating MicroRNAs Mus Muscle Cells Myocarditis Pathogenesis Pathway interactions Patients Penetrance Pharmaceutical Preparations Pharmacotherapy Play Preclinical Testing Production RNA Reporting Research Risk Role Signal Pathway Signal Transduction Sudden Death Testing Therapeutic Ventricular Work arrhythmogenic cardiomyopathy base cardiac muscle disease disease phenotype effective therapy efficacy testing exercise training experimental study genetic approach glycogen synthase kinase 3 beta heuristics immune activation in vivo Model induced pluripotent stem cell inhibitor/antagonist insight mouse model myocardial damage myocardial injury new therapeutic target pre-clinical prevent small molecule targeted treatment

项目摘要

Project Summary/Abstract The goal of this project is to define the role of inflammation in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a familial non-ischemic heart muscle disease that causes sudden death in the young and especially in athletes. Exercise accelerates disease penetrance, and increases arrhythmic risk and adverse cardiac events in ACM patients, but how exercise exacts this terrible toll is not known. We now report substantial new data showing that ACM disease alleles activate NFκB signaling in cardiac myocytes and that inhibition of this signaling pathway prevents the full ACM disease phenotype in a robust, well characterized mouse model. We also show that exercise greatly intensifies inflammatory signaling, thus providing a new mechanistic explanation for accelerated disease progression in athletes. These observations suggest that targeted anti-inflammatory therapy could be a powerful, truly mechanism-based approach to reduce adverse events in ACM patients. Accordingly, we will test the hypotheses that 1) activation of an innate immune response in cardiac myocytes mediated by NFκB causes arrhythmias and myocardial damage in ACM; and 2) exercise accelerates progression of ACM by stimulating production of injurious inflammatory mediators via activation of NFκB signaling in cardiac myocytes. In Aim 1, we will use genetic approaches in defined mouse models to elucidate the relative contributions to the ACM disease phenotype of activation of an immune response in cardiac myocytes vs. the actions of infiltrating inflammatory cells. In Aim 2, we will characterize effects of exercise on inflammation in ACM and define new mechanisms by which exercise promotes myocardial injury and arrhythmias. And in Aim 3, we will test the efficacy of selected FDA-approved drugs to prevent clinically important features of the ACM disease phenotype and mitigate the dangerous effects of exercise. We will also characterize expression of miRNAs that regulate NFκB and GSK3β signaling to identify RNA-based strategies to turn off inflammatory signaling. Such preclinical testing, we hope, will provide a pathway to future clinical trials in patients with ACM.

项目概要/摘要该项目的目标是确定炎症在致心律失常发病机制中的作用心肌病 (ACM)，一种导致年轻人猝死的家族性非缺血性心肌疾病尤其是对于运动员来说，运动会加速疾病的外显率，并增加心律失常的风险。 ACM 患者发生不良心脏事件，但运动如何导致这种可怕的后果尚不清楚。大量新数据表明 ACM 疾病等位基因激活心肌细胞中的 NFκB 信号传导，并且抑制该信号通路可防止 ACM 疾病以强健、特征明确的方式出现完整的表型我们还表明，运动会大大增强炎症信号，从而提供了一种新的方法。这些观察结果表明，运动员疾病加速进展的机制解释。靶向抗炎治疗可能是一种强大的、真正基于机制的方法，可以减少不良反应因此，我们将测试以下假设：1) 先天免疫的激活。 NFκB 介导的心肌细胞反应会导致 ACM 中的心律失常和心肌损伤；2) 运动通过刺激有害炎症介质的产生来加速 ACM 的进展心肌细胞中 NFκB 信号传导的激活在目标 1 中，我们将在特定小鼠中使用遗传方法。阐明免疫激活对 ACM 疾病表型的相对贡献的模型在目标 2 中，我们将描述心肌细胞的反应与浸润炎症细胞的作用。运动对 ACM 炎症的影响并确定运动促进炎症的新机制在目标 3 中，我们将测试 FDA 批准的选定药物对心肌损伤和心律失常的疗效。预防 ACM 疾病表型的临床重要特征并减轻危险影响我们还将表征调节 NFκB 和 GSK3β 信号传导的 miRNA 的表达，以进行识别。我们希望这种基于 RNA 的策略能够关闭炎症信号。未来 ACM 患者临床试验的途径。