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Autophagy in Alcoholic Pancreatitis

酒精性胰腺炎中的自噬

基本信息

批准号：
9925046
负责人：
Wen-Xing Ding
金额：
$ 34.43万
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：
2017
资助国家：
美国
起止时间：
2017-05-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925046
关键词：
Acetaldehyde Acetates Acinar Cell Acute Address Adenoviruses Agonist Alcohol abuse Alcohol consumption Alcoholic Pancreatitis Alcohols Amylases Antiinflammatory Effect Autophagocytosis Binding Biogenesis Blood CNR2 gene Cells Chronic Consumption Dependovirus Development Drug Kinetics Edema Enzyme Precursors Enzymes Esters Ethanol Metabolism Excision Exocrine pancreas Extracellular Signal Regulated Kinases FRAP1 gene Fatty Acids Goals Human Impairment In Vitro Infiltration Inflammatory Injury Intervention Intramural Research Program Kansas Knockout Mice Light Link Lipase Lysosomal Function Inhibition Lysosomes Mediating Medical center Microtubules Modeling Molecular Morbidity - disease rate Mus National Institute on Alcohol Abuse and Alcoholism Normal Cell Oral Outcome Pancreas Pancreatic enzyme Pancreatitis Pathogenesis Pathway interactions Pattern Pharmacology Pharmacology and Toxicology Process Proteins Protocols documentation Research Risk Factors Rodent Role Serum Testing Therapeutic Intervention Time Tissues Toxic effect Translations Trypsin Universities Zymogen Granules alcohol measurement cell injury chronic alcohol ingestion chronic pancreatitis clinical application cytokine feeding improved in vivo mortality mouse model novel novel therapeutics overexpression prevent problem drinker receptor repaired transcription factor

项目摘要

Project Summary Alcohol abuse is a major risk factor in initiating pancreatitis in humans and in rodents. Experimental evidence indicates that alcohol consumption leads to the destabilization of lysosomes and increases zymogen fragility in acinar cells. Cells can adapt and protect themselves by removing these damaged lysosomes and zymogen granules (ZGs) by autophagy and lysosomal biogenesis. However, these protective mechanisms are impaired after chronic alcohol consumption. Cannabinoid receptor 2 (CB2) agonists have potent anti-inflammatory effects and protect against experimental pancreatitis in mice. However, the underlying molecular mechanisms by which CB2 agonists protect against pancreatitis are not known. Moreover, what is also missing is the availability of CB2 agonists with optimal pharmacokinetics and absence of major toxicity as tested in relevant alcoholic pancreatitis models. In our preliminary studies, we established a novel alcohol pancreatitis mouse model using the recently established chronic plus acute alcohol binge (Gao-binge) protocol. Gao-binge induces significant pathogenesis in mouse pancreas, including edema, increased ZGs, elevated expression of inflammatory cytokines, increased infiltration of inflammatory cells and release of pancreatic enzymes (amylase and lipase) into the blood. We also demonstrated that Gao-binge decreases expression of pancreatic cannabinoid receptor 2 (CB2) and inactivates TFEB, a master regulator of lysosomal biogenesis. A selective CB2 agonist activates TFEB in mouse pancreas and increases autophagic flux in cultured acinar cells. Here we propose a novel hypothesis that ethanol metabolism leads to decreased CB2 expression and impaired TFEB-mediated lysosomal biogenesis, insufficient autophagy, accumulation of fragile ZGs, damaged lysosomes, and subsequent pancreatitis. Our long-term goal is to understand the molecular mechanisms for alcohol impairment of lysosomal biogenesis in pancreatic acinar cells, in order to identify steps in the repair pathway that are points for intervention in alcoholic pancreatitis. The objective of this proposal is to understand how CB2 agonists activate TFEB-mediated lysosomal biogenesis and selective zymophagy and lysophagy to protect against alcohol-induced pancreatitis. Using complimentary expertise in CB2 receptor pharmacology/toxicology (NIAAA intramural research program) and modeling of lysosomal biogenesis and alcoholic pancreatitis in vitro and in vivo (University of Kansas Medical Center) we propose to test a set of novel, highly selective and orally available CB2 agonists assuring quick translation toward clinical application for the treatment of alcoholic pancreatitis. We will determine how the selective CB2 agonists activate TFEB- mediated lysosomal biogenesis and their ability to improve the insufficient autophagy to remove damaged lysosomes and ZGs induced by chronic alcohol consumption. This proposal brings together research expertise that will address key research questions on alcoholic pancreatitis and the potential intervention by CB2 agonists, which would not otherwise be possible.

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。实验证据表明饮酒会导致溶酶体不稳定并增加酶原的脆弱性腺泡细胞。细胞可以通过去除这些受损的溶酶体和酶原来适应和保护自己通过自噬和溶酶体生物合成产生颗粒（ZG）。然而，这些保护机制受到损害长期饮酒后。大麻素受体 2 (CB2) 激动剂具有有效的抗炎作用作用并预防小鼠实验性胰腺炎。然而，潜在的分子机制 CB2 激动剂如何预防胰腺炎尚不清楚。此外，还缺少的是 CB2 激动剂的可用性具有最佳的药代动力学并且没有相关试验中的主要毒性酒精性胰腺炎模型。在我们的初步研究中，我们建立了一种新型酒精性胰腺炎小鼠使用最近建立的慢性加急性酗酒（Gao-binge）方案的模型。高狂欢诱发小鼠胰腺中的重要发病机制，包括水肿、ZG 增加、炎症细胞因子、炎症细胞浸润增加和胰酶释放（淀粉酶和脂肪酶）进入血液。我们还证明了高暴饮可以降低胰腺的表达大麻素受体 2 (CB2) 并使 TFEB 失活，TFEB 是溶酶体生物合成的主要调节因子。有选择性的 CB2 激动剂可激活小鼠胰腺中的 TFEB，并增加培养的腺泡细胞中的自噬通量。这里我们提出了一个新的假设，即乙醇代谢导致 CB2 表达减少并受损 TFEB 介导的溶酶体生物发生、自噬不足、脆弱 ZG 的积累、受损溶酶体，以及随后的胰腺炎。我们的长期目标是了解其分子机制酒精损害胰腺腺泡细胞溶酶体生物发生，以确定修复步骤途径是酒精性胰腺炎干预的重点。该提案的目的是了解 CB2 激动剂如何激活 TFEB 介导的溶酶体生物发生以及选择性酶噬和溶噬预防酒精引起的胰腺炎。利用 CB2 受体方面的互补专业知识药理学/毒理学（NIAAA 壁内研究计划）和溶酶体生物合成建模酒精性胰腺炎的体外和体内（堪萨斯大学医学中心）我们建议测试一组新型、高选择性、口服 CB2 激动剂，确保快速转化为临床应用用于治疗酒精性胰腺炎。我们将确定选择性 CB2 激动剂如何激活 TFEB- 介导的溶酶体生物发生及其改善自噬去除受损物质的能力长期饮酒诱导的溶酶体和 ZG。该提案汇集了研究专业知识这将解决酒精性胰腺炎的关键研究问题以及 CB2 的潜在干预措施激动剂，否则这是不可能的。