Alcohol and Muscle Stem Cells

酒精和肌肉干细胞

• 批准号: 7125620
• 负责人: GORDON S HUGGINS
• 金额: $ 28.85万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-25 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125620
• 关键词: alcohol dehydrogenase; cardiac myocytes; cell differentiation; cell proliferation; ethanol; genetically modified animals; laboratory mouse; laboratory rat; muscle satellite cell; myoblasts; myocardium disorder; regeneration; tissue /cell culture; toxin metabolism; transcription factor

DESCRIPTION (provided by applicant): Excessive alcohol intake is a leading cause of non-ischemic dilated cardiomyopathy. While the pathogenesis of alcoholic cardiomyopathy is poorly understood, a direct toxic role for alcohol and its principal metabolite acetaldehyde has been postulated. Until recently, the heart has been viewed as an organ formed from terminally differentiated cells. Data have emerged however to support the existence of cardiac- and extra-cardiac-derived stem cells capable of replacing dead myocardial cells. This proposal seeks to test the hypothesis that one central mechanism by which alcohol damages the heart is by impairing the ability of endogenous stem cells to replace damaged heart tissue. We propose to use cellular and whole animal approaches to test this hypothesis and to explore the potential use of cellular therapies for treatment of the alcohol-damaged heart. To begin our study we will seek to quantify cardiomyocyte stem cell replacement during alcohol exposure, as well the contribution of replacement cells derived from the bone marrow. Preliminary data presented in this application demonstrates that alcohol can directly affect skeletal satellite cell differentiation. We will extend these studies by exploring the effect of alcohol on progenitor cells isolated from the heart as well as the cardiomyocyte-specific differentiation of embryonic stem cells. Tissue-specific stem cell differentiation requires the coordinated input of lineage-determining transcription factors. As shown in our preliminary data, alcohol alone and in conjunction with the metabolic enzyme alcohol dehydrogenase (ADH), significantly reduces the transcriptional activity of the cardiac determination transcription factor GATA4. To better understand how alcohol may directly affect cardiac-specific stem cell differentiation we will study how alcohol affects GATA4-dependent transcription. Finally to better understand the impact of alcohol metabolism and acetaldehyde on cardiac stem cells we will study a transgenic line of mice that express alcohol dehydrogenase in the heart. By exposing heart progenitor cells to alcohol, with and without ADH overexpression, we will seek to better understand the effect of ethanol and its principal metabolite on progenitor cell proliferation and differentiation. To complete our analysis we will seek to correlate the contractile abnormalities of alcoholic myopathy with stem cell number, and then determine the role of exogenous stem cell replacement in the treatment of experimental alcoholic cardiomyopathy. Alcoholic cardiomyopathy remains a significant public health problem. Studies outlined in this application are designed to provide needed insight into the role of alcohol on stem cell-based tissue-repair.

描述（由申请人提供）：过量的酒精摄入量是非缺血性扩张心肌病的主要原因。虽然对酒精性心肌病的发病机理的理解很少，但已经假定了酒精及其主要代谢物乙醛的直接有毒作用。直到最近，心脏一直被视为由末端分化细胞形成的器官。但是，已经出现了数据，以支持能够替代死亡心肌细胞的心脏和心外衍生的干细胞的存在。该提议试图检验以下假设：一种中心机制通过损害内源性干细胞替代受损的心脏组织的能力而损害心脏的中心机制。我们建议使用细胞和整个动物方法检验这一假设，并探索细胞疗法的潜在用途来治疗酒精受损的心脏。为了开始我们的研究，我们将寻求在酒精暴露期间量化心肌细胞干细胞的置换，以及源自骨髓的替代细胞的贡献。本应用程序中提供的初步数据表明，酒精可以直接影响骨骼卫星细胞分化。我们将通过探索酒精对从心脏分离的祖细胞的影响以及胚胎干细胞的心肌细胞特异性分化来扩展这些研究。组织特异性干细胞分化需要谱系指定转录因子的协调输入。如我们的初步数据所示，单独使用酒精并与代谢酶醇脱氢酶（ADH）一起显着降低了心脏测定转录因子GATA4的转录活性。为了更好地了解酒精如何直接影响心脏特异性干细胞分化，我们将研究酒精如何影响GATA4依赖性转录。最终，为了更好地了解酒精代谢和乙醛对心脏干细胞的影响，我们将研究一小鼠的转基因系，该小鼠在心脏中表达酒精脱氢酶。通过将心脏祖细胞暴露于酒精，有或没有ADH过表达的情况下，我们将寻求更好地理解乙醇及其主要代谢产物对祖细胞增殖和分化的影响。为了完成我们的分析，我们将寻求将酒精性肌病的收缩异常与干细胞数相关联，然后确定外源干细胞替代在治疗实验性酒精性心肌病治疗中的作用。酒精性心肌病仍然是一个重大的公共卫生问题。本应用中概述的研究旨在提供有关酒精对干细胞基于干细胞组织修复的作用的必要洞察力。