The role of hormone-evoked mitochondrial calcium increases in the pathogenesis of

激素诱发的线粒体钙增加在发病机制中的作用

• 批准号: 7671508
• 负责人: LAWRENCE D GASPERS
• 金额: $ 35.1万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-10 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7671508
• 关键词: Acetaldehyde; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcohols; Animal Feed; Animal Model; Animals; Apoptosis; Apoptotic; Biochemical; Blood; Calcium; Catabolism; Catecholamines; Cell Death; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Coupled; Cytochromes; Cytosol; DNA-Binding Proteins; Data; Diet; Energy Metabolism; Ethanol; Ethanol toxicity; Figs - dietary; Fluorescence; Hepatocyte; Hormones; Imaging Techniques; Injury; Inositol; Lead; Liquid substance; Liver; Liver diseases; Luciferases; Measures; Mediating; Membrane Potentials; Metabolism; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Modification; Molecular; Molecular Biology; Morbidity - disease rate; NADH; Pathogenesis; Pathway interactions; Patients; Peptides; Phosphatidylinositols; Phospholipase C; Physiology; Play; Predisposition; Process; Production; Protein Isoforms; Proteins; Rattus; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Site; Staging; Stimulus; Tissues; Toxic effect; acetaldehyde dehydrogenase; adduct; cell injury; cell type; chronic alcohol ingestion; cytokine; cytotoxic; enzyme activity; feeding; fluorescence imaging; inhibitor/antagonist; insight; mitochondrial dysfunction; mitochondrial membrane; mortality; oxidation; problem drinker; pyridine nucleotide; receptor coupling; research study; response

DESCRIPTION (provided by applicant): Alcohol abuse has deleterious affects on almost every tissue in the body and is a major cause of morbidity and mortality worldwide. The acute actions of alcohol on cellular function are fully reversible whereas long-term alcohol intoxication can lead to irreversible tissue damage. The molecular mechanisms contributing to the onset and progression of irreversible cell injury are still poorly understood. In this application, we propose to investigate the hypothesis that adaptive changes in the phosphoinositide-dependent signaling pathway play a key role in the pathogenesis of alcohol-induced tissue injury. Our preliminary data indicate that feeding rats an ethanol-containing liquid diet (i.e., DeCarli-Lieber) for 60 days enhances the liver' sensitivity to hormones coupled to phospholipase C-¿. The addition of low concentrations of hormones evoked more sustained cytosolic calcium increases in hepatocytes isolated from alcohol-fed animals compared to their pairfed controls. Moreover, cells from alcoholic animals had a larger increase in inositol-1,4,5-trisphosphate (InsP3) formation following low hormone stimulation suggesting that chronic alcohol consumption altered phospholipase C-¿ activity. Normally, cytosolic calcium increases activate mitochondrial physiology to match ATP formation with utilization; however prolonged or inappropriate calcium increases can also lead to matrix calcium overload and mitochondrial dysfunction. Mitochondrial damage is a common feature observed in chronic alcoholic patients and animal models of alcohol abuse. Mitochondrial dysfunction may increase the tissues' susceptibility to other types of injury or apoptotic stimuli. This may be particularly important in chronic alcoholics that have elevated levels of TNFa, a proinflammatory cytokine, which evokes apoptotic cell death in hepatocytes through the mitochondrial-dependent pathway. In this proposal, we will (1) characterize the alcohol-induced alterations in phosphoinositide-dependent signaling pathway, (2) determine the effects of InsP3-dependent calcium increases on mitochondrial calcium levels and energy metabolism in control and chronically ethanol-fed rats and (3) determine the effects Ca2+-moblizing hormones on TNFa-induced apoptosis in hepatocytes from alcohol-fed rats and their pair-fed controls. The proposed studies will provide new insights into the adaptive responses evoked by the sustained presence of ethanol and the associated injurious consequences for the liver.

描述（由申请人提供）：酒精滥用对身体几乎每个组织都有有害影响，是全球发病率和死亡率的主要原因。酒精对细胞功能的急性作用是完全可逆的，而长期酒精中毒可导致不可逆的组织损伤。导致不可逆细胞损伤的发生和发展的分子机制仍然知之甚少。在本申请中，我们提出的假设，即适应性变化的磷酸肌醇依赖性信号通路在酒精诱导的组织损伤的发病机制中发挥了关键作用。我们的初步数据表明，给大鼠喂食含乙醇的液体饮食（即，DeCarli-Lieber）持续60天，增强了肝脏对磷脂酶C偶联激素的敏感性。添加低浓度的激素诱发更持续的细胞质钙离子增加，从酒精喂养的动物分离的肝细胞相比，他们的配对控制。此外，酒精动物的细胞在低激素刺激后，肌醇-1，4，5-三磷酸（InsP 3）的形成有较大的增加，这表明长期饮酒改变了磷脂酶C-<$的活性。通常，胞质钙增加激活线粒体生理学以使ATP形成与利用相匹配;然而，长期或不适当的钙增加也可导致基质钙超载和线粒体功能障碍。线粒体损伤是慢性酒精中毒患者和酒精滥用动物模型中观察到的共同特征。线粒体功能障碍可能会增加组织对其他类型损伤或凋亡刺激的易感性。这可能是特别重要的慢性酗酒者，具有升高水平的TNF α，一种促炎细胞因子，引起凋亡细胞死亡的肝细胞通过依赖性途径。在本研究中，我们将（1）描述酒精诱导的磷酸肌醇依赖性信号通路的改变，（2）确定InsP 3依赖性钙增加对对照和长期乙醇喂养大鼠线粒体钙水平和能量代谢的影响，（3）确定Ca 2+动员激素对酒精喂养大鼠及其配对对照肝细胞TNF α诱导的细胞凋亡的影响。拟议的研究将提供新的见解的适应性反应引起的持续存在的乙醇和相关的损害后果的肝脏。