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.

项目概要 酒精暴露是心脏发育异常的一个关键危险因素，并导致先天性心脏病， 婴儿死亡的主要非传染性原因。酒精引起的心脏生长发育受损 早年生活也会增加成年后患心脏病的风险。此外，成人的心脏系统也 对酒精暴露敏感，这是导致心脏病的一个重要但未被充分认识的危险因素 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由酒精的复杂作用引起的，包括 细胞毒性、氧化应激和异常 Ca2+ 处理增加。酒精产生的炎症细胞因子 暴露还可能导致酒精引起的心脏损伤。然而，酒精的潜在机制—— 诱发的心脏病尚未完全确定，并且缺乏有效的治疗方法。 传统上，由于可用性有限，关于酒精暴露的研究依赖于动物模型和细胞 和人原代心肌细胞的生长能力。然而，动物模型的研究非常耗时， 价格昂贵，不适合高通量药物筛选，并且由于生理原因而受到限制 与人类的差异。为了补充动物模型和细胞的研究，我们最近探索了 使用源自人类诱导多能干细胞（hiPSC-CM）的心肌细胞作为一种新型和 研究酒精引起的心脏毒性的生理相关模型。 hiPSC-CM 有许多相似的功能 人类原代CM，可以被设计成组织样结构并在长期培养物中维持，并且 可适用于高通量平台。 我们已经证明，将 hiPSC-CM 暴露于临床相关剂量的酒精可以重现 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病 异常的 Ca2+ 处理和收缩性表明功能障碍。我们已将 hiPSC-CM 改编成高 通量格式和建立的高通量测定法来检测酒精引起的心脏毒性和筛查 用于心脏增殖/保护剂。使用这种体外人体细胞模型和最先进的高科技 通量技术，我们建议研究酒精引起的毒性的潜在分子机制 人类心肌细胞并评估减轻酒精诱导的细胞毒性的潜在疗法。此外， 我们计划研究炎症细胞因子在酒精引起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 人类心肌细胞潜在的酒精毒性，并加速开发有针对性的有效药物 疗法。