Arrhythmogenic Cardiomyopathy is an Inflammatory Disease

致心律失常性心肌病是一种炎症性疾病

• 批准号: 10629180
• 负责人: JEFFREY E SAFFITZ
• 金额: $ 56.09万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629180
• 关键词: Acceleration; 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; Ventricular; Work; arrhythmogenic cardiomyopathy; 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; insight; mouse model; myocardial damage; myocardial injury; new therapeutic target; p38 Mitogen Activated Protein Kinase; pre-clinical; prevent; small molecule; targeted treatment; therapeutic RNA

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 尤其是在运动员中。运动会加速疾病的外显率，并增加心律失常的风险和 ACM 患者会出现不良心脏事件，但运动如何导致这种可怕的后果尚不清楚。我们现在报道 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 鼠标模型。我们还表明，运动极大地增强了炎症信号传导，从而提供了一种新的 运动员疾病加速进展的机制解释。这些观察表明 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 ACM 患者的事件。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导致 ACM 中的心律失常和心肌损伤；和 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 心肌细胞的反应与浸润炎症细胞的作用。在目标 2 中，我们将描述 运动对 ACM 炎症的影响并确定运动促进炎症的新机制 心肌损伤和心律失常。在目标 3 中，我们将测试 FDA 批准的选定药物的功效 预防 ACM 疾病表型的临床重要特征并减轻危险影响 锻炼。我们还将表征调节 NFκB 和 GSK3β 信号传导的 miRNA 的表达，以确定 基于 RNA 的策略来关闭炎症信号传导。我们希望此类临床前测试能够提供 未来 ACM 患者临床试验的途径。