Patient-specific modeling of metabolic dysfunction in statin-induced myopathy using iPSC-derived myocytes

项目总结/摘要 他汀类药物是目前应用最广泛的降胆固醇和预防冠心病的药物 心脏病然而，依从性很差;研究报告称，只有不到一半的患者服用他汀类药物， 规定的。他汀类药物依从性的主要障碍之一是与肌病相关的症状，包括 肌肉不适、无力和横纹肌溶解，这是一种潜在的危及生命的疾病。然而， 他汀类药物诱导的肌病（SIM）的机制仍然知之甚少，这是由于1）复杂的多效性， 他汀类药物的肌毒性作用，2）受影响患者肌细胞的可及性有限，以及3）缺乏适当的 动物模型，以研究他汀类药物毒性的差异敏感性。以前的临床和科学 研究结果表明，他汀类药物在线粒体中的脱靶效应是SIM的机制，但结果表明， 尚未在人体研究中得到验证。 从人iPSC产生骨骼肌细胞（SkMCs）的最新进展提出了一种新的方法， 前所未有的机会，模型骨骼肌疾病，如SIM。在此，我提议调查 通过使用患者特异性iPSC平台研究SIM的疾病机制。具体来说，我将测试中央 假设SIM是通过骨骼肌特异性脱靶效应介导的，导致线粒体氧化还原 失衡、代谢受损和随后的细胞死亡。在这项研究中，我将首先描述代谢 他汀类药物在iPSC衍生的SkMC和患者肌细胞中的作用（目的1）。然后我会调查 通过比较iPSC-SkMCs，研究患者特异性不同肌病对他汀类药物敏感性的机制 从耐受他汀类药物的患者到患有SIM的患者（目的2）。最后，我将确定小说 利用基因组规模的CRISPR干扰筛选技术在SIM发病机制中起关键作用的基因 通过特异性沉默与他汀类药物毒性有关的基因，从而赋予他汀类药物耐受性（Aim 3）。的 这项研究的结果将阐明SIM的分子机制，并促进精确的创建。 医学工具，以加强诊断，预防和治疗SIM。

Project Summary/Abstract Statins are the most widely used medication in reducing blood cholesterol and preventing coronary heart disease. However, adherence is poor; studies report fewer than half of patients take statins as prescribed. One of the main barriers in statin adherence is symptoms related to myopathy which include muscle discomfort, weakness, and rhabdomyolysis, a potentially life-threatening condition. Yet, the underlying mechanism of statin-induced myopathy (SIM) remains poorly understood due to 1) complex pleiotropic and myotoxic effects of statins, 2) limited accessibility of affected patients’ myocytes, and 3) lack of appropriate animal models to investigate the differential susceptibilities of statin toxicity. Previous clinical and scientific findings suggest off-target effects of statins in the mitochondria as the mechanism of SIM, but the results have not been validated in human studies. Recent advances in the generation of skeletal muscle cells (SkMCs) from human iPSCs present an unprecedented opportunity to model skeletal muscle diseases such as SIM. Herein, I propose to investigate the disease mechanisms of SIM by using a patient-specific iPSC platform. Specifically, I will test the central hypothesis that SIM is mediated via skeletal muscle-specific off-target effects resulting in mitochondrial redox imbalance, metabolic compromise and subsequent cell death. For this study, I will first characterize metabolic consequences of statins in iPSC-derived SkMCs and patient myocytes (Aim 1). I will then investigate the mechanism behind patient-specific differential myopathic susceptibility to statins by comparing iPSC-SkMCs derived from patients tolerant of statins to patients suffering from SIM (Aim 2). Finally, I will identify novel genes critical in the pathogenesis of SIM utilizing a genome-scale CRISPR interference screening technique by specifically silencing genes involved in statin toxicity and thereby conferring statin tolerance (Aim 3). The findings from this study will elucidate the molecular mechanism of SIM and facilitate the creation of precision medicine tools to enhance the diagnosis, prevention and treatment of SIM.