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

使用 iPSC 衍生的肌细胞对他汀类药物诱导的肌病代谢功能障碍进行患者特异性建模

• 批准号: 10666466
• 负责人: June-wha Rhee
• 金额: $ 13.72万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666466
• 关键词: Adherence; Affect; Animal Model; Area; Biochemical; Biological Assay; Biotechnology; Blood; CRISPR interference; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Death; Cell Differentiation process; Cell Line; Cell Membrane Permeability; Cell Respiration; Cells; Cholesterol; Clinic; Clinical; Code; Complex; Coronary heart disease; Coupled; Diagnosis; Disease; Endothelial Cells; Engineering; Evaluation; Gene Silencing; Generations; Genes; Genetic Determinism; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic study; Genotype; Glucose; Goals; Grant; Guide RNA; Homeostasis; Human; Injury; Investigation; Knowledge; Lead; Libraries; Life; Luciferases; Mediating; Medical; Medicine; Membrane Transport Proteins; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Molecular; Molecular Target; Monitor; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Myalgia; Myopathy; Nicotinamide adenine dinucleotide; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Predisposition; Prevention; Protocols documentation; Qi; Reaction; Reporter; Reporting; Research; Research Personnel; Research Training; Resistance; Rhabdomyolysis; Risk; Role; Skeletal Muscle; Stress; Symptoms; Techniques; Technology; Testing; Therapeutic; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Variant; cardiovascular health; cofactor; diagnostic tool; gene function; gene network; genome wide association study; genome-wide; improved; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; knock-down; loss of function; mitochondrial dysfunction; mitochondrial membrane; mouse model; novel; novel diagnostics; patient subsets; patient tolerability; pleiotropism; precision medicine; prevent; recruit; response; screening; side effect; skeletal; therapeutic target; tool; transcriptomics; uptake

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.

项目摘要/摘要 他汀类药物是降低血液胆固醇和预防冠状动脉的最广泛使用的药物 心脏病。但是，依从性很差。研究报告少于一半的患者将他汀类药物当作 规定。他汀类药物依从性的主要障碍之一是与肌病有关的符号，其中包括 肌肉不适，弱点和横纹肌溶解，潜在的威胁生命的疾病。但是，基础 他汀类药物诱导的肌病（SIM）的机制由于1）复杂的多效性和 他汀类药物的肌毒性作用，2）受影响患者的肌细胞的可及性有限，3）缺乏适当的 动物模型研究他汀类药物毒性的差异敏感性。以前的临床和科学 调查结果表明他汀类药物在线粒体中的靶向效应是SIM的机理，但结果具有 在人类研究中没有得到验证。 人IPSC的骨骼肌细胞（SKMC）产生的最新进展呈现 前所未有的机会来对骨骼肌疾病进行建模，例如SIM。在这里，我建议调查 使用患者特异性IPSC平台使用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，代谢折衷和随后的细胞死亡。对于这项研究，我首先将代谢特征 汀类药物在IPSC衍生的SKMC和患者心肌细胞中的后果（AIM 1）。然后我将调查 通过比较iPSC-SKMC，患者特异性差异的肌病敏感性的机制 源自他汀类药物的患者对患有SIM的患者的耐受性（AIM 2）。最后，我将确定小说 使用基因组尺度CRISPR干扰筛查技术对SIM的发病机理中至关重要的基因 通过特异性沉降基因与他汀类药物毒性有关，从而会议汀类药物的耐受性（AIM 3）。这 这项研究的发现将阐明SIM的分子机制并促进精确的创造 医学工具以增强SIM的诊断，预防和治疗。

项目成果

Self-assembled lipid--polymer hybrid nanoparticles: a robust drug delivery platform.

• DOI: 10.1021/nn800275r
• 发表时间: 2008-08
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Zhang, Liangfang;Chan, Juliana M.;Gu, Frank X.;Rhee, June-Wha;Wang, Andrew Z.;Radovic-Moreno, Aleksandar F.;Alexis, Frank;Langer, Robert;Farokhzad, Omid C.
• 通讯作者: Farokhzad, Omid C.

Race and Genetics in Congenital Heart Disease: Application of iPSCs, Omics, and Machine Learning Technologies.

• DOI: 10.3389/fcvm.2021.635280
• 发表时间: 2021
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Mullen M;Zhang A;Lui GK;Romfh AW;Rhee JW;Wu JC
• 通讯作者: Wu JC

Modeling Effects of Immunosuppressive Drugs on Human Hearts Using Induced Pluripotent Stem Cell-Derived Cardiac Organoids and Single-Cell RNA Sequencing.

• DOI: 10.1161/circulationaha.121.054317
• 发表时间: 2022-04-26
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Sallam, Karim;Thomas, Dilip;Gaddam, Sadhana;Lopez, Nicole;Beck, Aimee;Beach, Leila;Rogers, Albert J.;Zhang, Hao;Chen, Ian Y.;Ameen, Mohamed;Hiesinger, William;Teuteberg, Jeffrey J.;Rhee, June-Wha;Wang, Kevin C.;Sayed, Nazish;Wu, Joseph C.
• 通讯作者: Wu, Joseph C.

Sex-Specific Cardiovascular Risks of Cancer and Its Therapies.

• DOI: 10.1161/circresaha.121.319901
• 发表时间: 2022-02-18
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Wilcox NS;Rotz SJ;Mullen M;Song EJ;Ky Hamilton B;Moslehi J;Armenian SH;Wu JC;Rhee JW;Ky B
• 通讯作者: Ky B

Mitochondrial Dysfunction in Cardiac Arrhythmias.

• DOI: 10.3390/cells12050679
• 发表时间: 2023-02-21
• 期刊: Cells
• 影响因子: 6