Digestive enzyme misfolding promotes alcoholic pancreatitis

摘要 目前拨款提案的目的是证明先天基因突变是如何 使胰腺对酒精引起的损伤敏感，并导致酒精性胰腺炎。具体的 经检验的假说假设酒精和影响消化酶折叠的突变具有协同作用 促进内质网应激，导致进行性腺泡细胞损伤。在这 在这种情况下，胰腺对侮辱变得更加敏感，并以急性发作做出反应 炎症(酒精性急性胰腺炎)，最终发展为慢性病 (酒精性慢性胰腺炎)。我们提议的研究将利用一种新的基因 转基因小鼠品系，在小鼠羧基肽酶中携带“错误折叠”突变 A1(Cpa1)基因。我们将研究酒精饮食对自发性胰腺的影响。 实验性损伤、内质网应激标志物、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.