Digestive enzyme misfolding promotes alcoholic pancreatitis

消化酶错误折叠促进酒精性胰腺炎

• 批准号: 9927478
• 负责人: Miklos Sahin-Toth
• 金额: $ 21.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927478
• 关键词: Acinar Cell; Acute; Affect; Alcohol-Induced Disorders; Alcoholic Pancreatitis; Alcoholism; Alcohols; Amylases; Animals; Applications Grants; Arginine; C57BL/6N Mouse; Carboxypeptidase; Cell Death; Cells; Chronic; Chronic Disease; DNA Sequence Alteration; Development; Diet; Dropout; Edema; Enzymes; Event; Exhibits; Fibrosis; Gene Mutation; Genes; Genetic Predisposition to Disease; Genetic Risk; Genetically Engineered Mouse; Human; Induced Mutation; Infiltration; Inflammation; Inflammatory; Inherited; Injections; Injury; Liquid substance; Mediating; Molecular; Morphology; Mouse Strains; Mus; Mutation; Necrosis; Onset of illness; Pancreas; Pancreatic Diseases; Pancreatitis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Phenotype; Publishing; Risk; Serum; Severity of illness; Testing; Trypsin; Up-Regulation; acute pancreatitis; alcohol effect; alcoholic chronic pancreatitis; cell injury; chronic pancreatitis; endoplasmic reticulum stress; experimental study; feeding; gene environment interaction; genetic risk factor; innovation; lung injury; non-alcoholic; novel; novel diagnostics; novel therapeutic intervention; problem drinker; programs; response; synergism; tool

ABSTRACT The objective of the present grant proposal is to demonstrate how inborn gene mutations can sensitize the pancreas to alcohol-induced injury and result in alcoholic pancreatitis. The specific hypothesis tested posits that alcohol and mutations that affect digestive enzyme folding synergize in promoting endoplasmic reticulum stress and causing progressive acinar cell damage. In this setting, the pancreas becomes more sensitive to insults and responds with acute attacks of inflammation (alcoholic acute pancreatitis) which eventually progress to chronic disease (alcoholic chronic pancreatitis). Our proposed studies will take advantage of a novel genetically engineered mouse strain, which carries a “misfolding” mutation in the mouse carboxypeptidase A1 (Cpa1) gene. We will study how in this strain an alcohol diet affects spontaneous pancreatic damage, ER stress markers, cell death pathways and pathological responses in experimentally induced acute pancreatitis.

摘要