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

项目摘要/摘要 他汀类药物是应用最广泛的降胆固醇和预防冠状动脉病变的药物 心脏病。然而，依从性很差；研究报告称，只有不到一半的患者将他汀类药物作为 开了处方。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、虚弱和横纹肌溶解，这是一种潜在的危及生命的情况。然而，潜在的 他汀类药物诱导的肌病(SIM)的机制仍然知之甚少，原因是1)复杂的多效性和 他汀类药物的肌肉毒性作用，2)患者心肌细胞的可及性受限，3)缺乏适当的 用动物模型研究他汀类药物毒性的不同易感性。以往的临床和科学研究 研究结果表明，线粒体中他汀类药物的非靶点效应是SIM的机制，但结果 并未在人体试验中得到证实。 人IPSCs体外培养骨骼肌细胞的最新研究进展 为SIM等骨骼肌疾病建模提供了前所未有的机会。在此，我提议调查 使用针对患者的IPSC平台研究SIM的发病机制。具体地说，我将测试中央 SIM是通过骨骼肌特异的脱靶效应导致线粒体氧化还原而介导的假说 失衡、新陈代谢受损以及随后的细胞死亡。对于这项研究，我将首先描述新陈代谢 他汀类药物对IPSC来源的SkMCs和患者心肌细胞的影响(目标1)。然后我会调查 通过比较IPSC-SkMCs研究患者对他汀类药物的不同肌病敏感性的机制 来源于对他汀类药物耐受的患者对SIM患者(目标2)。最后，我将鉴定小说 应用基因组规模CRISPR干扰筛选技术研究SIM发病机制中的关键基因 通过特异性地沉默参与他汀类药物毒性的基因，从而增强他汀类药物的耐受性(目标3)。这个 这项研究的发现将阐明SIM的分子机制，并有助于创造精确度 加强对SIM的诊断、预防和治疗的医学工具。

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.