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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）：三分之一的酒精滥用者表现出心脏收缩力和肌肉力量下降，分别称为酒精性心肌病和肌病，在美国约有600万人。事实上，心肌病伴充血性心力衰竭最常见的原因是慢性酒精中毒。然而，这些疾病的发病机制仍然不清楚。对人类酗酒者和动物模型的研究表明，长期饮酒会增加氧化应激和其他细胞应激因子，并增强对细胞凋亡的易感性。除了我们证明了酒精中毒患者的骨骼肌和心脏细胞凋亡率显著增加外，我们还显示了酒精喂养动物的心脏功能下降。我们的初步数据表明，乙醇也干扰了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，乙醇诱导的致敏细胞凋亡/坏死可能会改变微妙的细胞之间的平衡生存和细胞死亡。我们推测，慢性酒精滥用敏感的心脏和肌肉线粒体凋亡引起的钙超载和投标至少部分通过增强氧化/亚硝化应激。我们认为，慢性酒精滥用也会影响骨骼肌中祖细胞介导的再生，骨骼肌是一种具有强大再生能力的器官。因此，我们认为细胞死亡和更新之间的平衡受损是酒精性心肌病和骨骼肌病变发展的核心。本申请的目的是i）评价来自人类酗酒者和喂食乙醇的大鼠的心脏和骨骼肌中的应激反应标志物和细胞凋亡/坏死，重点是线粒体应激途径，和ii）将这些参数与酒精性组织损伤的程度相关联，和iii）确定乙醇对骨骼肌中祖细胞数量、增殖和分化的影响。我们已经收集了来自西班牙巴塞罗那医院诊所生命支持系统患者的精确注释的人类心脏和骨骼肌组织，并继续获得更多标本。我们还与NIAAA氧化应激和组织损伤部门负责人Pacher博士建立了富有成效的合作关系，他是心血管系统氧化/亚硝化应激研究的领导者。因此，PI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通过氧化/亚硝化应激方面的专业知识和获得独特的人类组织资源来补充。此外，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。我们希望这些研究的结果将提供一个独特的桥梁的机制之间的酒精诱导的组织损伤的动物模型和人类酗酒者，并将揭示酒精性心肌病和肌病的发病机制。