Novel mechanisms of regulating endoplasmic reticulum homeostasis in alcoholic pancreatitis

调节酒精性胰腺炎内质网稳态的新机制

基本信息

批准号：
10742433
负责人：
Wen-Xing Ding
金额：
$ 40.69万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10742433
关键词：
2019-nCoV Acinar Cell Alcohol abuse Alcohol consumption Alcoholic Hepatitis Alcoholic Pancreatitis Alcoholic beverage heavy drinker Alcohols Attenuated Autophagocytosis Autophagosome Binding Biogenesis Cell Death Cells Cholesterol Complication Coronavirus Infections Development Drosophila genus Dyslipidemias Endoplasmic Reticulum Enzymes Equilibrium Excision Exocrine pancreas Foundations Genetic Goals Homeostasis Human Human Genome Impairment Integral Membrane Protein Intestines Knock-in Mouse Lipids Lipoproteins Liver Mediating Membrane Proteins Messenger RNA Modeling Molecular Morbidity - disease rate Mus Organelles Outcome Pancreas Pancreatitis Pathogenesis Pathologic Phosphatidylserines Prevention Protein Biosynthesis Protein Secretion Proteins Quality Control Risk Factors Rodent Role Testing Transcriptional Activation Vacuole Zebrafish alcohol effect cell injury endoplasmic reticulum stress feeding genome wide association study improved mortality mouse model novel novel therapeutic intervention novel therapeutics pharmacologic phospholipid scramblase promoter reconstitution transcription factor

项目摘要

Project Summary Alcohol abuse is a major risk factor in initiating pancreatitis in humans and in rodents. However, only less than 10% of heavy drinkers develop alcoholic pancreatitis whereas most heavy drinkers have mild and autolimited pathological changes, suggesting that a refined adaptation in pancreatic cells to protect against the detrimental effects of alcohol. Pancreatic exocrine acinar cells possess high protein synthetic rates to produce and secrete large amounts of digestive enzymes. To meet the high demand of protein synthesis, acinar cells are exceptionally enriched with endoplasmic reticulum (ER). Dysregulation of ER homeostasis can lead to ER stress and acinar cell damage resulting in the onset of pancreatitis. Cells use protective mechanisms such as autophagy to balance the homeostasis of organelles such as ER to adapt and protect themselves from ER stress. Defective basal autophagy in mouse pancreas disrupts ER homoeostasis resulting in ER stress and spontaneous pancreatitis. We recently demonstrated that transcription factor EB (TFEB) directly regulates lysosomal biogenesis and, indirectly, autophagy, which is impaired by alcohol causing alcoholic hepatitis and pancreatitis. Our preliminary studies showed that alcohol feeding decreased VMP1 (vacuole membrane protein 1), an ER-resident multispanning transmembrane protein, at both mRNA and protein levels in an experimental alcohol pancreatitis mouse model. More importantly, acinar cell-specific deletion of VMP1 in mice leads to increased ER stress and spontaneous pancreatitis. Damaged and excess ER can be removed via selective autophagy, termed as ER-phagy, which helps to maintain ER homeostasis and relieve ER stress. Our long- term goal of this proposal is to understand the molecular mechanisms for how alcohol decreases VMP1 in acinar cells and how VMP1-mediated autophagy protects against alcohol-induced pancreatitis. The objective of this proposal is to understand how VMP1-mediated ER-phagy is impaired by alcohol in acinar cells and how to pharmacologically maintain acinar cell ER homeostasis to protect against alcohol-induced pancreatitis. We will determine how genetic and pharmacological activation of TFEB-VMP1-mediated ER-phagy regulates ER homeostasis and protects against alcohol-induced pancreatitis. This proposal will establish a foundation for the development of novel therapeutics for treating alcoholic pancreatitis through modulation of VMP1-mediated ER-phagy to maintain acinar cell organelle homeostasis.

项目概要酗酒是引发人类和啮齿动物胰腺炎的主要危险因素。然而，仅小于 10% 的重度饮酒者会患上酒精性胰腺炎，而大多数重度饮酒者患有轻度和自限性胰腺炎病理变化，表明胰腺细胞进行了精细的适应以防止有害的损害酒精的影响。胰腺外分泌腺泡细胞具有高蛋白质合成率来生产和分泌大量的消化酶。为了满足蛋白质合成的高需求，腺泡细胞内质网 (ER) 异常丰富。 ER 稳态失调可导致 ER 压力和腺泡细胞损伤导致胰腺炎的发生。细胞使用保护机制，例如自噬平衡细胞器（如 ER）的稳态，以适应和保护自身免受 ER 影响压力。小鼠胰腺的基础自噬缺陷破坏了内质网稳态，导致内质网应激和自发性胰腺炎。我们最近证明转录因子 EB (TFEB) 直接调节溶酶体生物发生和间接自噬，酒精会损害自噬，导致酒精性肝炎和胰腺炎。我们的初步研究表明，饮酒会降低VMP1（液泡膜蛋白） 1)，一种内质网驻留的多跨膜蛋白，在实验中在 mRNA 和蛋白质水平上酒精性胰腺炎小鼠模型。更重要的是，小鼠中腺泡细胞特异性删除 VMP1 会导致内质网应激增加和自发性胰腺炎。受损和多余的 ER 可以通过选择性去除自噬，称为内质网自噬，有助于维持内质网稳态并缓解内质网应激。我们的长期该提案的长期目标是了解酒精如何降低 VMP1 的分子机制腺泡细胞以及 VMP1 介导的自噬如何预防酒精诱发的胰腺炎。的目标该提案旨在了解腺泡细胞中酒精如何损害 VMP1 介导的 ER 吞噬以及如何药理上维持腺泡细胞内质网稳态，以预防酒精诱发的胰腺炎。我们将确定 TFEB-VMP1 介导的 ER 吞噬的遗传和药理学激活如何调节 ER 体内平衡并预防酒精引起的胰腺炎。该提案将为通过调节 VMP1 介导的治疗酒精性胰腺炎的新疗法的开发内质网吞噬维持腺泡细胞器稳态。