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。已有研究表明，饮酒模式会影响 酒精引起的器官损伤的影响。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，这一领域的研究进展受到了阻碍。我们 最近开发了一种长期酗酒暴露的范例，在这种范例中，酒精导致胰腺 急性胰腺炎的损害特征。我们既没有长期酗酒，也没有酗酒 造成了严重的胰腺损伤。然而，慢性加酗酒暴露导致了剧烈的胰腺 损伤和炎症，并伴有内质网应激。ER是网站上的 蛋白质的折叠、修饰和运输，以及钙的储存。内质网应激是由内质网的变化引起的 动态平衡，如蛋白质合成增加，错误折叠的蛋白质积累，或钙的变化 级别。内质网应激触发未折叠蛋白反应(UPR)，其功能是恢复内质网内稳态。然而， 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。我们进一步展示了 长期酒精暴露抑制了MANF的表达，MANF是内质网应激反应的关键蛋白 最初被认为是一种神经营养因子，主要作用是维持内质网的动态平衡。我们假设 MANF是一种关键的UPR组件，可以缓解因酒精暴露而产生的内质网应激，以及慢性 酒精暴露会损害MANF，导致对内质网应激的易感性增加。我们提出了两个具体目标 来检验这些假说。特定目的1确定MANF在慢性/酗酒诱导中的作用 胰腺受损。特定目标2确定内质网应激在慢性/暴饮暴食中是否起关键作用 酒精暴露会对胰腺造成损害。作为一个单位，该提案将使用新的动物模型来 探讨慢性/酗酒暴露所致胰腺损伤的机制。这项研究 将不仅深入了解酒精性胰腺炎的细胞/分子机制，而且还将建立 MANF的保护作用。因此，它可能为酒精中毒的治疗提供一个潜在的新靶点。 胰腺炎。