Alcohol-induced cardiac injury and repair in human induced pluripotent stem cell model

人诱导多能干细胞模型中酒精引起的心脏损伤和修复

• 批准号: 10209255
• 负责人: Chunhui Xu
• 金额: $ 35.18万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-20 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209255
• 关键词: Adult; Affect; Alcohol consumption; Alcohols; Animal Model; Anti-Arrhythmia Agents; Antioxidants; Apoptosis; Arrhythmia; CXCL12 gene; Calcium; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cell Death; Cell model; Cells; Chemicals; Clinical; Complement; Complex; Consumption; Development; Dose; Effectiveness; Embryonic Development; Engineering; Ethanol; Ethanol toxicity; Event; Fetal Alcohol Exposure; Fetus; Gene Expression; Genes; Goals; Growth; Growth and Development function; Heart; Heart Abnormalities; Heart Diseases; Heart Injuries; Human; Impairment; In Vitro; Infant Mortality; Inflammation; Inflammatory; Investigational Therapies; Ion Channel; Lead; Libraries; Life; Link; Machine Learning; Modeling; Molecular; Myocardial dysfunction; National Institute on Alcohol Abuse and Alcoholism; Natural regeneration; Organ; Oxidative Stress; Pathologic; Phenotype; Physiological; Pilot Projects; Play; Property; Protective Agents; Response Elements; Risk; Risk Factors; Role; RyR2; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Signal Transduction; Stromal Cell-Derived Factor 1; Structure; System; TNF gene; Technology; Testing; Time; Tissues; Toxic effect; Woman; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; appropriate dose; cardiogenesis; clinically relevant; congenital heart disorder; cytokine; cytotoxicity; effective therapy; heart cell; heart disease risk; heart function; high throughput screening; high throughput technology; high-throughput drug screening; human pluripotent stem cell; human stem cells; induced pluripotent stem cell; injury and repair; interest; new therapeutic target; novel; novel therapeutics; nuclear factor-erythroid 2; small molecule; small molecule libraries; stem cell model; stem cells; targeted treatment; transcription factor; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Alcohol exposure is a key risk factor for abnormal heart development and contributes to congenital heart disease, the leading non-infectious cause of infant mortality. Alcohol-induced impaired heart growth and development in early life can also increase the risk of heart disease later in adulthood. Furthermore, adult cardiac system is also sensitive to alcohol exposure, which is an important but underappreciated risk factor contributing to heart disease. Alcohol exposure is associated with ischemic events, arrhythmias and alterations in cardiac function and structure. These pathological consequences could result from complex actions of alcohol including increased cytotoxicity, oxidative stress and abnormal Ca2+ handling. Inflammatory cytokines produced by alcohol exposure could also contribute to alcohol-induced heart injury. However, mechanisms underlying alcohol- induced heart disease are not fully defined and effective therapies are lacking. Traditionally, studies on alcohol exposure have relied on animal models and cells because of limited availability and growth capacity of human primary cardiomyocytes. However, studies in animal models are time consuming, expensive, and not amenable for high-throughput drug screening, and have limitations due to physiological differences from humans. To complement the studies on animal models and cells, we have recently explored the use of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) as a novel and physiologically relevant model to study alcohol-induced cardiotoxicity. hiPSC-CMs have many features similar to human primary CMs, can be engineered into tissue-like structures and maintained in long-term cultures, and can be adapted for high-throughput platforms. We have demonstrated that exposure of hiPSC-CMs with clinically relevant doses of alcohol can recapitulate pathological events caused by alcohol exposure, including oxidative stress, altered gene expression and cardiac dysfunction as indicated by abnormal Ca2+ handling and contractility. We have adapted hiPSC-CMs into high- throughput formats and established high-throughput assays to detect alcohol-induced cardiotoxicity and screen for cardiac proliferative/protective agents. Using this in vitro human cell model and state-of-the-art high- throughput technologies, we propose to investigate underlying molecular mechanisms of alcohol-induced toxicity in human cardiomyocytes and evaluate potential therapies to mitigate alcohol-induced cytotoxicity. In addition, we plan to investigate the involvement of inflammatory cytokines in alcohol-induced cardiac injury and repair. We expect that our established hiPSC-CM model will help understand the molecular and cellular mechanisms underlying alcohol toxicity in human cardiomyocytes and accelerate the development of targeted and effective therapies.

项目总结 酒精暴露是心脏发育异常的关键风险因素，并导致先天性心脏病， 婴儿死亡的主要非传染性原因。酒精对大鼠心脏生长发育的影响 早年生活也会增加成年后患心脏病的风险。此外，成人心脏系统也是 对酒精暴露敏感，这是一个重要但被低估的风险因素，有助于心脏 疾病。酒精暴露与缺血事件、心律失常和心功能改变有关 和结构。这些病理后果可能是酒精的复杂行为造成的，包括 细胞毒性增加，氧化应激和异常的钙离子处理。酒精产生的炎性细胞因子 暴露也可能导致酒精引起的心脏损伤。然而，酒精背后的机制- 诱发性心脏病还没有完全定义，也缺乏有效的治疗方法。 传统上，对酒精暴露的研究依赖于动物模型和细胞，因为可获得性有限 和人原代心肌细胞的生长能力。然而，在动物模型中进行研究是耗时的， 价格昂贵，不适合高通量药物筛选，而且由于生理原因而有局限性 与人类的不同。为了补充对动物模型和细胞的研究，我们最近探索了 人诱导多能干细胞来源的心肌细胞(hiPSC-CMS)作为一种新型和 研究酒精心脏毒性的生理相关模型。HiPSC-CMS具有许多相似的特征 到人类原代CMS，可以被工程化为组织样结构，并在长期培养中保持，以及 可适用于高吞吐量平台。 我们已经证明，暴露于临床相关剂量的酒精的HiPSC-CMS可以概括为 酒精暴露引起的病理事件，包括氧化应激、基因表达改变和心脏 功能障碍，表现为钙离子处理和收缩能力异常。我们已经将HiPSC-CMS改造成高- 建立并建立了检测酒精所致心脏毒性和筛选的高通量分析方法 用于心脏增殖剂/保护剂。使用这种体外人体细胞模型和最先进的高科技 技术，我们建议研究酒精毒性的潜在分子机制。 并评估减轻酒精诱导的细胞毒性的潜在治疗方法。此外, 我们计划研究炎性细胞因子在酒精诱导的心脏损伤和修复中的作用。 我们期望我们建立的HiPSC-CM模型将有助于理解分子和细胞机制 酒精对人心肌细胞的潜在毒性及加速发展的靶向性和有效性 治疗。