Cell Death in Alcoholic Heart and Muscle

酒精导致的心脏和肌肉细胞死亡

基本信息

批准号：
8460010
负责人：
Gyorgy Hajnoczky
金额：
$ 32.33万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8460010
关键词：
Abstinence Accounting Affect Alcohol abuse Alcoholic Cardiomyopathy Alcoholic Intoxication Alcoholism Alcohols Animal Feed Animal Model Animals Apoptosis Apoptotic BCL2 gene Basic Science Biopsy Calcium Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Caspase Cell Count Cell Culture Techniques Cell Death Cell Fraction Cell Survival Cells Cellular Stress Cellular Stress Response Cessation of life Chronic Clinical Research Clinics and Hospitals Collaborations Collection Complement Congestive Heart Failure Consumption Data Development Diet Dilated Cardiomyopathy Disease Doxorubicin Echocardiography Equilibrium Ethanol Exhibits Heart Heat shock proteins Human Imaging Techniques Incidence Individual Injury Left Ventricular Ejection Fraction Life Support Systems Light Measurement Mediating Membrane Methods Mitochondria Modeling Muscle Cells Muscle Fibers Muscle Weakness Myocardium Myopathy National Institute on Alcohol Abuse and Alcoholism Natural regeneration Necrosis Organ Oxidative Stress Pathogenesis Pathologic Pathway interactions Patients Permeability Persons Phase Predisposition Production Protein Family Rattus Reactive Nitrogen Species Reactive Oxygen Species Research Resolution Sampling Scheme Signal Pathway Skeletal Muscle Skeletal Muscle Satellite Cells Skeletal muscle injury Source Spain Specimen Stem cells Stress Testing Time Tissues alcohol effect alcoholic myopathy biological adaptation to stress chronic alcohol ingestion cytochrome c endonuclease enhancing factor equilibration disorder experience feeding fluorescence imaging hemodynamics human AMID protein human tissue interdisciplinary collaboration mitochondrial membrane muscle strength nitrosative stress problem drinker progenitor public health relevance response response marker satellite cell skeletal skeletal muscle differentiation stress protein therapeutic target tissue resource

项目摘要

DESCRIPTION (provided by applicant): One third of alcohol abusers manifest decreased cardiac contractility and muscle strength termed respectively alcoholic cardiomyopathy and myopathy, accounting for about 6 million persons in the US. In fact, the most common cause of cardiomyopathy with congestive heart failure is chronic alcoholism. However, the pathogenesis of these conditions still remains obscure. Studies in human alcoholics and animal models have demonstrated that chronic ethanol consumption increases oxidative stress and other cellular stress factors and enhances the susceptibility to apoptosis. In addition to our demonstration of a marked increase in the rate of apoptosis in human skeletal muscle and heart from alcoholic patients, we have also shown decreased cardiac function in alcohol-fed animals. Our preliminary data indicate that ethanol also interferes with the proliferation and differentiation o skeletal muscle satellite cells and other stem cells in culture. These findings suggest that ethanol-induced sensitization to apoptosis/necrosis may alter the delicate cellular equilibrium between survival and cell death. We hypothesize that chronic alcohol abuse sensitizes heart and muscle to mitochondrial apoptosis elicited by Ca2+ overload and Bid at least in part by enhancing oxidative/nitrosative stress. We propose that chronic alcohol abuse also affects renewal mediated by progenitor cells in skeletal muscle, an organ that has a robust capacity for regeneration. Thus we propose that an impaired balance between cell death and renewal are central to the development of alcoholic cardiomyopathy and skeletal myopathy. The aims of this application are to i) evaluate stress response markers and apoptosis/necrosis in heart and skeletal muscle from human alcoholics and rats fed ethanol, with an emphasis on the mitochondrial stress pathways and ii) relate these parameters to the degree of alcoholic tissue injury, and iii) determine the effects of ethanol on progenitor cell number, proliferation and differentiation in skeletal muscle. We have available a collection of precisely annotated human heart and skeletal muscle tissues derived from patients on life support systems at the Hospital Clinic in Barcelona, Spain, and continue to obtain additional specimens. We have also established a productive collaboration with Dr. Pacher, the Chief of the Oxidative Stress and Tissue Injury Unit at NIAAA, who is a leader in research of oxidative/nitrosative stress in the cardiovascular system. Thus, the PIs' experience in calcium and Bcl-2 family protein-mediated mitochondrial stress and the pathologic aspects of human alcoholic cardiomyopathy and myopathy will be complemented by expertise in oxidative/nitrosative stress and by access to a unique human tissue resource. Furthermore, the studies will employ the recent advances in high resolution, high capacity and semi-automatic fluorescence imaging. We expect that the results of these studies will provide a unique bridge between the mechanisms underlying alcohol-induced tissue injury in animal models and in human alcoholics and will shed light on the pathogenesis of alcoholic cardiomyopathy and myopathy.

描述（由申请人提供）：三分之一的饮酒者表现出降低的心脏收缩性和肌肉力量，分别称为酒精性心肌病和肌病，在美国约占600万人。实际上，心脏病和充血性心力衰竭的最常见原因是慢性酒精中毒。但是，这些条件的发病机理仍然晦涩难懂。人类酒精中毒和动物模型的研究表明，慢性乙醇消耗会增加氧化应激和其他细胞应激因素，并增强对凋亡的敏感性。除了表明人类骨骼肌和酒精患者心脏凋亡率显着增加外，我们还显示出饮酒动物的心脏功能降低。我们的初步数据表明，乙醇还干扰了培养物中的骨骼肌卫星细胞和其他干细胞的增殖和分化。这些发现表明，乙醇诱导的对凋亡/坏死的敏化可能会改变生存和细胞死亡之间细腻的细胞平衡。我们假设慢性酒精滥用使心脏和肌肉对Ca2+过载引起的线粒体凋亡敏感，并且至少部分通过增强氧化/硝化应激而出价。我们建议，慢性酒精滥用还会影响骨骼肌中祖细胞介导的更新，这是一种具有强大再生能力的器官。因此，我们建议细胞死亡与更新之间的平衡受损是酒精性心肌病和骨骼肌病的发展至关重要的。该应用的目的是i）评估人类酒精中毒的心脏和骨骼肌的应力反应标记和凋亡/坏死，并重点介绍了线粒体应力途径，ii）将这些参数与酒精组织损伤的程度相关联，以及III的程度，以及III），确定了乙醇对乙醇的影响，对乙醇的效应，以及在延速群中的效果，以及在甲醇中的效果，以及在甲醇中的效果，以及在甲醇中的效果，并在甲醇中造成了分数，并在数字上不同。我们提供了来自西班牙巴塞罗那医院诊所的生命支持系统患者的精确注释的人心脏和骨骼肌组织的集合，并继续获得其他标本。我们还与NIAAA的氧化应激和组织损伤部门负责人Pacher博士建立了一项富有成效的合作，他是心血管系统中氧化/硝化应激研究的领导者。因此，PIS在钙和Bcl-2家族蛋白介导的线粒体应激以及人类酒精性心肌病和肌病的病理方面的经验将得到氧化/硝化应激方面的专业知识以及获得独特的人体组织资源的补充。此外，这些研究将采用高分辨率，高容量和半自动荧光成像的最新进展。我们预计这些研究的结果将在动物模型和人类酒精中毒中提供的机制之间提供独特的桥梁，并阐明酒精性心肌病和肌病的发病机理。