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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

基本信息

批准号：
10599235
负责人：
Chunhui Xu
金额：
$ 35.21万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10599235
关键词：
Acceleration Adult Affect Alcohol consumption Alcohols Animal Model Anti-Arrhythmia Agents Antioxidants Apoptosis Arrhythmia 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 Ischemia 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 Proliferating 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 cardiac repair 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 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

项目摘要

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