Arrhythmogenic Cardiomyopathy is an Inflammatory Disease

项目总结/摘要 该项目的目标是确定炎症在致炎性结肠炎发病机制中的作用， 心肌病（ACM），一种家族性非缺血性心肌疾病，可导致年轻人猝死 尤其是运动员。运动会加速疾病的消退，并增加患病的风险， ACM患者的不良心脏事件，但运动如何导致这种可怕的代价尚不清楚。我们现在报告说 大量新数据显示ACM疾病等位基因激活心肌细胞中NFκB信号传导， 这种信号通路的抑制防止了完整的ACM疾病表型， 小鼠模型我们还表明，运动大大加强炎症信号，从而提供了一个新的 运动员疾病进展加速的机制解释。这些观察提示 靶向抗炎治疗可能是一种有效的，真正基于机制的方法，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 在ACM中，由NFκB介导的心肌细胞反应导致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加速ACM的进展， 心肌细胞中NFκB信号的激活。在目标1中，我们将在定义的小鼠中使用遗传方法， 模型来阐明免疫激活对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ACM炎症的影响，并确定运动促进ACM炎症的新机制。 心肌损伤和心律失常。在目标3中，我们将测试选定的FDA批准的药物的疗效， 预防ACM疾病表型的临床重要特征，并减轻 锻炼的我们还将描述调节NFκB和GSK 3 β信号传导的miRNA的表达， 基于RNA的策略来关闭炎症信号。我们希望，这样的临床前测试将提供一个 ACM患者未来临床试验的途径。

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.