Digestive enzyme misfolding promotes alcoholic pancreatitis

摘要 目前的拨款提案的目的是证明先天基因突变如何能够 使胰腺对酒精诱导的损伤敏感并导致酒精性胰腺炎。具体 假设检验假定酒精和影响消化酶折叠的突变协同作用 促进内质网应激并导致进行性腺泡细胞损伤。在这 在这种情况下，胰腺对损伤变得更加敏感，并以急性胰腺炎发作作为反应。 炎症（酒精性急性胰腺炎），最终进展为慢性疾病 （酒精性慢性胰腺炎）。我们提出的研究将利用一种新的基因， 工程小鼠品系，其在小鼠羧肽酶中携带“错误折叠”突变， A1（Cpa1）基因。我们将研究酒精饮食如何影响这种菌株的自发胰腺炎， 损伤，ER应激标志物，细胞死亡途径和病理反应， 诱发急性胰腺炎

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.