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: 10379358
• 负责人: JEFFREY E SAFFITZ
• 金额: $ 52.16万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379358
• 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; 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; insight; mouse model; myocardial damage; myocardial injury; new therapeutic target; 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.

项目摘要/摘要 本项目的目标是明确炎症在致心律失常的发病机制中的作用。 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 尤其是在运动员身上。运动会加速疾病的传导，增加心律失常的风险 ACM患者的不良心脏事件，但运动如何造成这一可怕的损失尚不清楚。我们现在报道 大量新数据表明，急性心肌梗死的等位基因激活了心肌细胞中的NFκB信号，并且 抑制这一信号通路可以预防ACM疾病的全部表型 老鼠模型。我们还表明，运动大大增强了炎症信号，从而提供了一种新的 运动员疾病进展加速的机制解释。这些观察结果表明 靶向抗炎治疗可能是一种有效的、真正基于机制的方法来减少不良反应 急性心肌梗塞患者发生的事件。因此，我们将检验以下假设：1)激活一种先天免疫 核因子κB介导的心肌细胞反应可引起急性心肌梗死的心律失常和心肌损伤； 运动通过刺激创伤性炎症介质的产生加速ACM的进展 心肌细胞中核因子κB信号的激活。在目标1中，我们将在已定义的小鼠中使用遗传方法 模型阐明免疫激活对ACM疾病表型的相对贡献 心肌细胞的反应与浸润性炎症细胞的作用。在目标2中，我们将描述 运动对急性心肌炎炎症反应的影响及运动促进的新机制 心肌损伤和心律失常。在目标3中，我们将测试选定的FDA批准的药物的有效性，以 预防ACM疾病表型的临床重要特征并减轻 锻炼身体。我们还将表征调节NFκB和GSK3β信号的miRNA的表达，以确定 基于RNA的策略，以关闭炎症信号。我们希望，这种临床前试验将提供一种 ACM患者未来临床试验的途径。