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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.

项目总结