Smoking, Alcohol Abuse and the Pancreas

吸烟、酗酒与胰腺

• 批准号: 8698308
• 负责人: STEPHEN J PANDOL
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698308
• 关键词: Acinar Cell; Address; Alcohol abuse; Alcoholic Pancreatitis; Alcoholic beverage heavy drinker; Alcohols; Binding; Binding Proteins; Biochemical Process; Boxing; Cell physiology; Cells; Chemistry; Clinical; Development; Disease; Drug abuse; Endoplasmic Reticulum; Ensure; Epidemiologic Studies; Ethanol; Ethanol Metabolism; Event; Exocrine pancreas; Failure; Functional disorder; Genetic; Habits; In Vitro; Individual; Ingestion; Intervention; Intracellular Transport; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Measurement; Metabolism; Mus; Mutation; Normal Cell; OmpR protein; Organ; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Pancreas; Pancreatitis; Pathologic; Pathology; Patients; Population; Post-Translational Protein Processing; Prevention; Process; Proteins; RNA Splicing; Rattus; Regulation; Research; Risk; Role; Signal Transduction; Smoker; Smoking; Stress; System; Testing; Up-Regulation; Veterans; Work; addiction; alcohol consequences; alcohol response; base; cellular pathology; cigarette smoking; design; endoplasmic reticulum stress; environmental stressor; feeding; in vivo; in vivo Model; novel; prevent; problem drinker; protein metabolism; research study; response; reticulum cell; synthetic protein

DESCRIPTION (provided by applicant): The mechanisms underlying the effects of alcohol abuse and smoking on the development of pancreatitis are poorly understood. Recent epidemiologic studies demonstrate that smoking accelerates the development of pancreatitis in alcoholic patients and may have an additive or multiplicative effect when combined with alcohol abuse to cause pancreatitis. We have recently demonstrated that alcohol metabolism causes an oxidative stress in the endoplasmic reticulum (ER) of the exocrine pancreatic acinar cell and that the acinar cell adapts to this stress through a system of adaptive responses in the ER called the Unfolded Protein Response (UPR). Specific genetic alteration to block an alcohol metabolism-dependent upregulation of spliced X-box binding protein 1 (XBP1-S), a key UPR regulator, induced dysregulation of the adaptive UPR, ER dysfunction and acinar cell pathology. These results suggest a central role of ER stress and the UPR induced by alcohol metabolism in the mechanism of pancreatitis due to alcohol abuse. Based on preliminary studies using smoking compounds we hypothesize that smoking compounds augment the development of alcoholic pancreatitis by accelerating redox disorders in the Endoplasmic Reticulum (ER) of the acinar cell and preventing key responses of the Unfolded Protein Response (UPR) from adapting the cell to the combination of both environmental stressors. To address this hypothesis, we propose both in vitro and in vivo models of alcohol abuse and smoking with measurements of ER stress, UPR and pathologic responses. Importantly, we plan to also use state-of-the-art approaches in chemistry and mass spectroscopy to assess alterations in key oxido-reductases that are essential for post- translational modifications of proteins in the lumen of the ER caused by alcohol abuse and smoking. Our approach is designed to reveal the consequences of alcohol and smoking compound metabolism in the ER of the acinar cell including both adaptive mechanisms and failure of the adaptive responses leading to pathologic consequences. The results will provide novel understanding on the early cellular events involved in diseases resulting from alcohol and smoking addiction and as such will provide opportunities for designing clinical interventions. Furthermore, our results should have broad ranging impacts on a variety of disorders related to abuse of these substances.

描述（由申请人提供）： 知识渊博，滥用酗酒和吸烟对胰腺炎发展的机制。最近的流行病学研究表明，吸烟加速了酒精患者的胰腺炎的发展，并且与酗酒结合起来引起胰腺炎时可能具有添加剂或乘法。我们最近证明，酒精代谢在外分泌胰腺腺泡细胞的内质网（ER）中引起氧化应激，并且腺泡细胞通过ER中的自适应反应系统适应了这种应激，称为ER中称为未折叠的蛋白质反应（UPR）。特定的遗传改变，以阻止酒精代谢依赖性的X-box结合蛋白1（XBP1-S）（XBP1-S）的上调（一种关键的UPR调节剂）诱导自适应UPR，ER功能障碍和腺泡病理病理学的失调。这些结果表明，ER应激的核心作用和酒精代谢引起的UPR在由于酗酒而引起的胰腺炎机理中。 基于使用吸烟化合物的初步研究，我们假设吸烟化合物通过加速腺泡细胞内胞质网状（ER）中的氧化还原疾病来增强酒精性胰腺炎的发展，并防止在环境应力的组合中，以使外向蛋白质反应（UPR）的关键反应（UPR）的关键反应。 为了解决这一假设，我们提出了酗酒和吸烟的体外和体内模型，并测量了ER压力，UPR和病理反应。重要的是，我们计划还使用化学和质谱法中的最先进方法来评估关键氧化还原酶的改变，这对于因酒精滥用和吸烟而引起的ER的蛋白质的转化后修饰至关重要。我们的方法旨在揭示腺泡细胞中酒精和吸烟复合代谢的后果，包括适应性机制以及导致病理后果的自适应反应的失败。 结果将为饮酒和吸烟成瘾引起的疾病涉及的早期细胞事件提供新的了解，因此将为设计临床干预提供机会。此外，我们的结果应该对与滥用这些物质有关的各种疾病产生广泛的影响。