MECHANISMS FOR ALCOHOL-INDUCED PANCREATIC DAMAGE

酒精引起的胰腺损伤的机制

• 批准号: 10251520
• 负责人: JIA LUO
• 金额: $ 9.94万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251520
• 关键词: MECHANISMS; ALCOHOL; INDUCED; PANCREATIC; DAMAGE

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.

酗酒是胰腺炎的主要危险因素。已经表明，饮酒方式影响了 酒精引起的器官损伤的影响。但是，潜在的细胞和分子机制仍然存在 不清楚。缺乏适当的动物模型阻碍了这一研究的进展。我们 最近已经开发了一种慢性加酒精暴露的范式，酒精引起胰腺 急性胰腺炎的损伤特征。我们既不显示慢性酒精暴露 造成严重的胰腺损伤。但是，慢性加苦酒暴露于诱导的急性胰腺 损害和炎症，伴随着内质网（ER）应力。 ER是 蛋白质折叠，修饰和传输以及钙储存。 ER压力是由ER的改变引起的 稳态，例如蛋白质合成的增加，错误折叠蛋白的积累或钙的变化 水平。 ER应力触发展开的蛋白质反应（UPR），该反应可恢复ER稳态。然而， 持续的ER压力超过了UPR恢复ER稳态的能力，从而导致细胞死亡。我们进一步显示 慢性酒精暴露抑制了MANF的表达，MANF是一种键应力的反应蛋白，是 最初被鉴定为神经营养因素和功能，主要是为了维持ER稳态。我们假设 该MANF是一个关键的UPR组件，可以缓解因酒精暴露而减轻ER压力，慢性 酒精暴露会损害MANF，从而增加对ER应力的敏感性。我们提出了两个具体目标 检验这些假设。特定目标1确定MANF在慢性/暴饮精酒暴露诱导的 损坏胰腺。特定目标2确定ER应力在慢性/暴饮暴食中是否起着关键作用 酒精暴露会引起胰腺的损害。作为一个单位，该提案将使用新颖的动物模型 研究慢性/暴饮暴食诱导的胰腺损伤的机制。研究 不仅会深入了解酒精性胰腺炎的细胞/分子机制，而且还建立了一个 Manf的保护作用。因此，它可能为酒精治疗提供潜在的新治疗靶点 胰腺炎。