Digestive enzyme misfolding promotes alcoholic pancreatitis

消化酶错误折叠促进酒精性胰腺炎

基本信息

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
项目类别：
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

项目摘要

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.

抽象的本赠款提案的目的是证明先天基因突变如何将pal骨敏感到酒精引起的损伤，并导致酒精性胰腺炎假设测试假设认为影响消化酶折叠的酒精和突变协同在促进内质网应激并引起进行性腺泡细胞损伤设置，pal夫对侮辱变得更加敏感，并以急性攻击的反应发炎（酒精性急性胰腺炎）最终发展为慢性病（酒精性慢性胰腺炎）。工程的小鼠应变，在小鼠羧基酶中带有“突变”突变 A1（CPA1）基因。损伤，ER应力标记，细胞死亡途径和实验性的病理反应诱发急性胰腺炎。