Mechanisms for alcohol-induced pancreatic damage

酒精引起的胰腺损伤的机制

• 批准号: 9753077
• 负责人: JIA LUO
• 金额: $ 7.89万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753077
• 关键词: Acinar Cell; Affect; Alcohol abuse; Alcohol-Induced Disorders; Alcoholic Pancreatitis; Alcohols; Animal Model; C57BL/6 Mouse; Calcium; Cell Death; Characteristics; Chronic; Cicatrix; Clinical; Control Groups; Data; Diabetes Mellitus; Diagnosis; Diet; Disease; Endoplasmic Reticulum; Ethanol; Exocrine pancreas; Gastrointestinal Diseases; Homeostasis; Hospitalization; Hospitals; Impairment; Inflammation; Inflammatory; Liquid substance; Modification; Molecular; Morbidity - disease rate; Mus; Organ; Pain; Pancreas; Pancreatitis; Pattern; Play; Predisposition; Protective Agents; Protein Biosynthesis; Proteins; Research; Resistance; Risk Factors; Role; Site; Symptoms; Testing; United States; Wild Type Mouse; acute pancreatitis; alcohol effect; alcohol exposure; alcohol response; chronic pancreatitis; drinking; endoplasmic reticulum stress; inhibitor/antagonist; insight; misfolded protein; mortality; neurotrophic factor; new therapeutic target; novel; novel therapeutic intervention; protein folding; response; restoration

Alcohol abuse is the major risk factor for pancreatitis. It has been shown that the drinking pattern affects the impact of alcohol-induced organ damage. However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research has been hindered by the lack of appropriate animal models. We have recently developed a paradigm of chronic plus binge alcohol exposure in which alcohol caused pancreatic damage characteristic of acute pancreatitis. We showed neither chronic nor binge alcohol exposure alone caused significant pancreatic damage. However, chronic plus binge alcohol exposure induced drastic pancreatic damage and inflammation which was accompanied by endoplasmic reticulum (ER) stress. ER is the site for protein folding, modification and transport, and calcium storage. ER stress is caused by the alterations in ER homeostasis, such as increased protein synthesis, accumulation of misfolded proteins, or changes in the calcium levels. ER stress triggers unfolded protein response (UPR) which functions to restore ER homeostasis. However, sustained ER stress exceeds UPR’s ability to restore ER homeostasis, resulting in cell death. We further showed that chronic alcohol exposure inhibited the expression of MANF, a key ER stress responsive protein which was originally identified as a neurotrophic factor and functions primarily to maintain ER homeostasis. We hypothesize that MANF is a critical UPR component that can alleviate ER stress in response to alcohol exposure, and chronic alcohol exposure impairs MANF, resulting in increased susceptibility to ER stress. We propose two specific aims to test these hypotheses. Specific Aim 1 determines the role of MANF in chronic/binge alcohol exposure-induced damage to the pancreas. Specific Aim 2 determines whether ER stress plays a critical role in chronic/binge alcohol exposure-induced damage to the pancreas. As a unit, the proposal will use novel animal models to investigate the mechanisms underlying chronic/binge alcohol exposure-induced pancreatic damage. The study will not only gain insight into cellular/molecular mechanisms of alcoholic pancreatitis but also establish a protective role of MANF. It therefore may offer a potential new therapeutic target for the treatment of alcoholic pancreatitis.

酒精滥用是胰腺炎的主要危险因素。研究表明，饮酒模式会影响 酒精引起的器官损伤。然而，潜在的细胞和分子机制仍然存在， 不清楚由于缺乏合适的动物模型，这一研究领域的进展受到阻碍。我们 最近开发了一种慢性加酗酒暴露的范例，其中酒精引起胰腺炎， 急性胰腺炎特有的损伤。我们既没有发现慢性酒精暴露， 造成了严重的胰腺损伤然而，慢性加酗酒暴露诱导了剧烈的胰腺炎， 损伤和炎症，伴随内质网（ER）应激。ER是用于 蛋白质折叠、修饰和运输以及钙储存。内质网应激是由内质网的改变引起的 稳态，如蛋白质合成增加，错误折叠蛋白质的积累，或钙离子的变化， 程度.内质网应激触发未折叠蛋白反应（UPR），其功能是恢复内质网稳态。然而，在这方面， 持续的内质网应激超过了UPR恢复内质网稳态的能力，导致细胞死亡。我们进一步研究发现 慢性酒精暴露抑制MANF的表达，MANF是一种关键的ER应激反应蛋白， 最初被鉴定为神经营养因子，其功能主要是维持ER稳态。我们假设 MANF是一个关键的UPR成分，可以缓解ER应激反应酒精暴露，慢性 酒精暴露损害MANF，导致对ER应激的敏感性增加。我们提出两个具体目标 来验证这些假设特异性目的1确定MANF在慢性/狂欢性酒精依赖诱导的 胰腺损伤。具体目标2确定ER应激是否在慢性/暴食中起关键作用 酒精引起的胰腺损伤作为一个单位，该提案将使用新的动物模型， 研究慢性/酗酒引起的胰腺损伤的机制。研究 将不仅深入了解酒精性胰腺炎的细胞/分子机制， MANF的保护作用。因此，它可能为治疗酒精中毒提供一个潜在的新靶点。 胰腺炎