MOLECULAR MECHANISMS OF PANCREATITIS

描述：初步数据支持激活与 应激激活蛋白激酶途径，趋化因子的表达，以及 促分泌剂诱导的实验性胰腺炎。这项工作的目的是 探索这些途径中事件之间的机制和相互关系 以及它们在胰腺炎中的作用。第一个目标是测试 腺泡内特异性快速诱导趋化因子的假说 利用促分泌剂诱发胰腺炎的治疗方法 胆管内注射胆盐和蛋白水解酶的过度刺激模型 和胰腺炎的缺血/再灌注模型。第二个目标 探讨了应激蛋白激酶途径激活是 对趋化因子基因表达的刺激是充分和必要的。 这将利用胰腺炎的活体动物模型以及 分散的胰腺腺泡细胞的体外研究。后者允许 应激蛋白激酶的激活和抑制的多种操作 信号级联反应，以及腺病毒介导的基因传递 体质活性或显性负性信号基因。第三个目标 验证NFkB参与趋化因子基因表达的假说 胰腺腺泡细胞。这再次利用了体内和体外两种方法 NFkB和IKB的各种操作方法。最终目标测试 假设体内趋化因子表达的修饰将 影响胰腺炎的严重程度。这将尝试利用 腺病毒载体直接表达特异性趋化因子的研究 并探讨活体胰腺对胰腺炎的影响特点。

DESCRIPTION: Preliminary data supports an association between activation of stress-activated protein kinase pathway, expression of chemokines, and secretagogue-induced experimental pancreatitis. This work is designed to explore mechanisms and interrelationships between events in these pathways and their role in pancreatitis. The first aim is designed to test the hypothesis that chemokines are specifically and rapidly induced in acinar cells by treatments that induce pancreatitis utilizing the secretagogue hyperstimulation model, intraductal injection of bile salt and protease solutions, and ischemia/reperfusion models of pancreatitis. The second aim explores the hypothesis that activation of the stress kinase pathway is necessary and sufficient for the stimulation of chemokine gene expression. This will utilize both the in vivo animal models of pancreatitis, as well as in vitro studies with dispersed pancreatic acinar cells. The latter allows various manipulations for activation and inhibition of stress kinase signalling cascades, as well as the adenoviral-mediated gene delivery of constitutively-active or dominant-negative signalling genes. The third aim tests the hypotheses that NFkB is involved in chemokine gene expression in pancreatic acinar cells. This again utilizes both in vivo and in vitro approaches with various manipulations of NFkB and IkB. The final aim tests the hypothesis that modification of chemokine expression in vivo will influence the severity of pancreatitis. This will attempt to utilize adenoviral vectors to directly express the specific chemokines in the pancreas in vivo and explore effects on the characteristics of pancreatitis.