Pathogenic Mechanisms of Pancreatitis

胰腺炎的发病机制

基本信息

批准号：
9021640
负责人：
Rodger A. Liddle
金额：
$ 34.58万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-21 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9021640
关键词：
Acinar Cell Acinus organ component Acute Afferent Neurons Agonist Alcoholic Pancreatitis Alcohols Amylases Anabolism Animal Model Arachidonate 5-Lipoxygenase Bile Acids Bile fluid Caerulein Calcium Calcium ion Cations Cell physiology Cells Cessation of life Cholelithiasis Coupled Critical Pathways Data Data Reporting Disease Enzymes Esters Ethanol Event Fatty Acids GTP-Binding Proteins Genes Genetic Health Human In Vitro Inflammation Inflammatory Infusion procedures Injury Lead Leukotriene B4 Ligands Ligation Link Mediating Methods Modeling Mouse Strains Mus Nerve Neurogenic Inflammation Neuropeptides Pain Pancreas Pancreatic duct Pancreatitis Pathogenesis Pathway interactions Play Predisposing Factor Production Protein Inhibition Protein secretory trypsin inhibitor Regulation Regulatory Pathway Role Signal Transduction Source Substance P System Testing Time Transgenic Mice Trypsin Trypsinogen Tyrosine Phosphorylation Vanilloid Work acute pancreatitis afferent nerve autocrine base chelation improved in vivo insight intense pain knockout gene mouse model neuromechanism new therapeutic target novel novel therapeutics overexpression receptor response

项目摘要

DESCRIPTION (provided by applicant): Acute pancreatitis is poorly understood and there are no good treatments for it. New insight into y mechanisms by which the pancreas is damaged by inflammatory insults may lead to better treatments for acute pancreatitis in people. There is strong evidence that neurogenic inflammation mediated by TRPV1 cation channels in a class of sensory neurons that innervate the pancreas play a role in acute pancreatitis, but the source of activation of TRPV1 is unknown. We have recently discovered that leukotriene B4 (LTB4), an endogenous agonist ligand of TRPV1, is produced by pancreatic acinar cells. Moreover, we have shown that LTB4 can induce pancreatitis an effect that is blocked by TRPV1 antagonists. In the current proposal we will test the hypothesis that LTB4 mediates acute pancreatic inflammation using several animal models: (1) caerulein hyperstimulation, (2) intraductal bile acid infusion, and (3) ethanol plus fatty acid ethyl ester administration. The intraductal bile aci infusion model is considered to be a good model of human gallstone- induced pancreatitis and the ethanol plus fatty acid ethyl ester model may be relevant to human alcohol- induced pancreatitis. The first specific aim is to test the hypothesis that 5-lipoxygenase (5-LO) and LTB4 mediate neurogenic inflammation in the three animal models described above. The second specific aim is to test the hypothesis that calcium-dependent and calcium-independent pathways are involved in 5-LO activation in these models. The third specific aim is to test the hypothesis that TRPV1 expressed by pancreatic acinar cells plays a role in acute pancreatitis in animal models. Experimental approaches to testing these hypotheses include in vivo induction of pancreatitis in mice, pharmacological stimulation and inhibition of various pathways of regulation, use of mouse strains with genetic deletions of TRPV1 and 5-LO genes, including pancreas specific knockouts of these genes, and in vitro studies of signal transduction mechanisms and regulation of 5- LO activity in pancreatic acini. We expect these studies will unveil a novel pathway critical to the pathogenesis of neurogenic pancreatitis. Importantly, these results may identify novel therapeutic targets for treating human acute pancreatitis.

描述（由申请人提供）：人们对急性胰腺炎知之甚少，并且没有好的治疗方法。对炎症损伤胰腺损伤机制的新见解可能会为人类急性胰腺炎提供更好的治疗方法。有强有力的证据表明，支配胰腺的一类感觉神经元中的 TRPV1 阳离子通道介导的神经源性炎症在急性胰腺炎中发挥作用，但 TRPV1 的激活来源尚不清楚。我们最近发现白三烯 B4 (LTB4) 是 TRPV1 的内源性激动剂配体，由胰腺腺泡细胞产生。此外，我们还发现 LTB4 可以诱发胰腺炎，但 TRPV1 拮抗剂可以阻断这种作用。在当前的提案中，我们将使用几种动物模型来测试 LTB4 介导急性胰腺炎症的假设：（1）雨伞素过度刺激，（2）导管内胆汁酸输注，以及（3）乙醇加脂肪酸乙酯给药。导管内胆汁aci输注模型被认为是人胆石诱发的胰腺炎的良好模型，而乙醇加脂肪酸乙酯模型可能与人酒精诱发的胰腺炎有关。第一个具体目标是检验 5-脂氧合酶 (5-LO) 和 LTB4 在上述三种动物模型中介导神经源性炎症的假设。第二个具体目标是检验这些模型中钙依赖性和钙非依赖性途径参与 5-LO 激活的假设。第三个具体目标是检验胰腺腺泡细胞表达的 TRPV1 在动物模型中在急性胰腺炎中发挥作用的假设。检验这些假设的实验方法包括在小鼠体内诱导胰腺炎、药理学刺激和抑制各种调节途径、使用具有 TRPV1 和 5-LO 基因遗传删除的小鼠品系，包括这些基因的胰腺特异性敲除，以及胰腺腺泡信号转导机制和 5-LO 活性调节的体外研究。我们预计这些研究将揭示一条对神经源性胰腺炎发病机制至关重要的新途径。重要的是，这些结果可能会确定治疗人类急性胰腺炎的新治疗靶点。