热休克蛋白GRP78途径调节的急性胰腺炎炎症反应的机制研究

项目名称： 热休克蛋白GRP78途径调节的急性胰腺炎炎症反应的机制研究

项目编号： No.81200286

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 张伟

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 急性胰腺炎的发病机制迄今未完全明确，在急性胰腺炎时，内质网应激和GRP78蛋白表达升高，而GRP78升高后可能通过诱导凋亡机制稳定内质网，从而减轻胰腺和全身其他脏器的毒性反应。 本课题运用体内实验，验证在急性胰腺炎的状态下，胰腺腺泡细胞发生内质网应激，GRP78蛋白参与诱导细胞凋亡；寻找内质网应激以及GRP78蛋白引起凋亡的通路，并分别运用酪氨酸激酶抑制剂诱导GRP78表达以及钙离子拮抗剂下调GRP78表达，观察急性胰腺炎后，内质网应激现象中的PERK-Pi、PEK-Pi、eIF2α-Pi、GADD43、CHOP等因子表达情况，以及胰腺和其他脏器损伤情况。同时，收集急性胰腺炎患者体液标本，观察GRP78和凋亡蛋白表达与患者胰腺损伤及其预后的相关性，尝试为急性胰腺炎的发病机制和临床治疗提供新的诊断思路和治疗依据。

中文关键词： 急性胰腺炎；内质网应激；凋亡；尼莫地平；

英文摘要： Pancreatitis remains a disease with significant morbidity and lethality,Its pathogenesis is incompletely understood.Endoplasmic reticulum stress and the increase of GRP78 may be responsible for the progress of pancreatitis.It is speculated that the induction of GRP78 after pancreatitis may be a survival mechanism that confers protection from subsequent stress and potentially aids in the refolding of intracellular proteins that were damaged during acute pancreatitis.The aim of this study is to investigate the relationship among GRP78 protein, endoplasmic reticulum and acute pancreatitis. In-vivo experiments will be conducted to detect the the fuction of GRP78 protein throngh the pathway of the induction of apoptosis in pancreatic acinar cells during the state of acute pancreatitis. Furthermore, the expression of protein factors including PEK-Pi, eIF2α-Pi, GADD43 and CHOP will be studied by using the GRP78 agonist ,tyrosine kinase inhibitor, and the GRP78 inhibitor,the calcium antagonists.And the damage of pancreas and other organs will also be observed as well. At the same time, body fluid specimens of patients with acute pancreatitis will be collected. The expression of GRP78 and apoptosis related proteins will also be investigated.We try to provide new thought for the pathogenesis and clinical treatm

英文关键词： acute pancreatitis；endoplasmic reticulum stress；apoptosis；nimodipine；