Smoking, Alcohol Abuse and the Pancreas

描述（由申请人提供）： 酒精滥用和吸烟对胰腺炎发生的影响的潜在机制知之甚少。最近的流行病学研究表明，吸烟加速了酒精中毒患者胰腺炎的发展，当与酒精滥用相结合时，可能会产生叠加或倍增效应，导致胰腺炎。我们最近已经证明，酒精代谢导致氧化应激的内质网（ER）的外分泌胰腺腺泡细胞和腺泡细胞适应这种压力，通过一个系统的适应性反应在ER称为展开蛋白质反应（UPR）。特异性遗传改变阻断酒精代谢依赖性上调剪接的X-box结合蛋白1（XBP1-S），一个关键的UPR调节，诱导适应性UPR，ER功能障碍和腺泡细胞病理失调。这些结果表明，ER应激和酒精代谢诱导的UPR在酒精滥用性胰腺炎的机制中起着重要作用。 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质网（ER）中的氧化还原障碍和阻止未折叠蛋白反应（UPR）的关键反应使细胞适应两种环境应激因素的组合来增强酒精性胰腺炎的发展。 为了解决这一假设，我们提出了在体外和体内模型的酒精滥用和吸烟与ER应激，UPR和病理反应的测量。重要的是，我们还计划使用化学和质谱的最先进方法来评估关键氧化还原酶的改变，这些氧化还原酶对于由酒精滥用和吸烟引起的ER管腔中蛋白质的翻译后修饰至关重要。我们的方法旨在揭示酒精和吸烟化合物在腺泡细胞ER中代谢的后果，包括适应性机制和导致病理后果的适应性反应失败。 这些结果将为酒精和吸烟成瘾引起的疾病所涉及的早期细胞事件提供新的理解，因此将为设计临床干预措施提供机会。此外，我们的研究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。

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.