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

• 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
• 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

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.

项目摘要 酒精滥用是引发人类和啮齿动物胰腺炎的主要危险因素。然而，只有不到 10%的重度饮酒者发生酒精性胰腺炎，而大多数重度饮酒者发生轻度和自动限制性胰腺炎。 病理变化，表明胰腺细胞的精细适应，以防止有害的 酒精的影响。胰腺外分泌腺泡细胞具有较高的蛋白质合成速率， 大量的消化酶。为了满足蛋白质合成的高需求，腺泡细胞 特别富含内质网（ER）。ER稳态失调可导致ER 压力和腺泡细胞损伤导致胰腺炎发作。细胞使用保护机制，如 自噬以平衡细胞器如ER的稳态，以适应和保护自身免受ER的侵害 应力小鼠胰腺中有缺陷的基础自噬破坏ER稳态，导致ER应激， 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的自噬，这是由酒精引起的酒精性肝炎受损， 胰腺炎我们的初步研究表明，酒精喂养降低了VMP 1（液泡膜蛋白 1），ER驻留的多跨膜蛋白，在mRNA和蛋白质水平在实验中， 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缺失VMP 1导致 ER应激增加和自发性胰腺炎。损坏和多余的ER可以通过选择性的 自噬，称为ER-吞噬，其有助于维持ER稳态和缓解ER应激。我们长久以来- 这项提案的长期目标是了解酒精如何降低VMP 1的分子机制， 腺泡细胞和VMP 1介导的自噬如何保护酒精诱导的胰腺炎。的目标 本研究的目的是了解酒精如何损害腺泡细胞中VMP 1介导的ER-吞噬，以及如何 酒精能维持腺泡细胞内质网的稳态，防止酒精性胰腺炎的发生。我们将 确定TFEB-VMP 1介导的ER吞噬的遗传和药理学激活如何调节ER 体内平衡和防止酒精诱导的胰腺炎。该提案将为 开发通过调节VMP 1介导的治疗酒精性胰腺炎的新疗法 ER-吞噬以维持腺泡细胞器的稳态。