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展的影响的潜在机制尚不清楚。最近的流行病学研究表明，吸烟加速了酗酒患者胰腺炎的发展，当与酒精滥用结合起来导致胰腺炎时，可能会产生相加或乘法效应。我们最近证实，酒精代谢导致胰腺外分泌腺泡细胞内质网(ER)的氧化应激，腺泡细胞通过ER中的一种称为未折叠蛋白反应(UPR)的适应性反应系统来适应这种应激。特异性的基因改变，以阻止依赖酒精代谢的剪接的X-box结合蛋白1(XBP1-S)的上调，一个关键的UPR调节因子，诱导适应性UPR的失调，内质网功能障碍和腺泡细胞病理。这些结果表明，内质网应激和酒精代谢诱导的UPR在酒精滥用所致胰腺炎的发病机制中起核心作用。基于对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)的氧化还原紊乱和阻止未折叠蛋白反应(UPR)的关键反应使细胞适应这两种环境应激源而增加酒精性胰腺炎的发生。为了解决这一假设，我们提出了酒精滥用和吸烟的体外和体内模型，并测量了内质网应激、UPR和病理反应。重要的是，我们还计划使用最先进的化学和质谱学方法来评估关键氧化还原酶的变化，这些氧化还原酶对于酒精滥用和吸烟引起的内质网管腔中蛋白质的翻译后修饰是必不可少的。我们的方法旨在揭示酒精和吸烟在腺泡细胞内质网中化合物代谢的后果，包括适应性机制和导致病理后果的适应性反应的失败。这一结果将对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，并因此为设计临床干预措施提供机会。此外，我们的结果应该对与滥用这些物质有关的各种障碍产生广泛的影响。

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.