Pathogenic Mechanisms of Pancreatitis

胰腺炎的发病机制

• 批准号: 8702876
• 负责人: Rodger A. Liddle
• 金额: $ 34.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/8702876
• 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; 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; overexpression; public health relevance; receptor; response

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）：急性胰腺炎知之甚少，没有很好的治疗方法。对胰腺受炎症性损伤损害的Y机制的新见解可能会导致人们更好地治疗人们急性胰腺炎。有充分的证据表明，在一类感觉神经元中TRPV1阳离子通道介导的神经源性炎症，这些神经元中胰腺支配胰腺在急性胰腺炎中起作用，但TRPV1的激活来源尚不清楚。我们最近发现，白细胞B4（LTB4）是TRPV1的内源性激动剂配体，由胰腺腺泡细胞产生。此外，我们已经表明LTB4可以诱导胰腺炎，这种作用被TRPV1拮抗剂阻断。在当前的提案中，我们将测试LTB4使用多种动物模型介导急性胰腺炎症的假设：（1）Caerulein降低过度刺激，（2）胆汁胆汁酸输注，以及（3）乙醇加脂肪酸乙基酯。导管内胆汁ACI输注模型被认为是人类胆结石诱导的胰腺炎的良好模型，乙醇加脂肪酸乙基酯模型可能与人类酒精诱导的胰腺炎有关。第一个具体目的是检验以下三种动物模型中5-脂氧合酶（5-LO）和LTB4介导神经源性炎症的假设。第二个具体目的是检验以下假设：在这些模型中，钙依赖性和独立于钙的途径参与5-LO激活。第三个具体目的是检验以下假设：胰腺腺泡细胞表达的TRPV1在动物模型中在急性胰腺炎中起作用。测试这些假设的实验方法包括小鼠中胰腺炎的体内诱导，药理学刺激以及抑制各种调节途径，使用TRPV1和5-LO基因的遗传缺失的小鼠菌株，包括这些基因的胰腺特异性敲除，以及这些基因的特定敲除以及信号转导机构的体外研究。我们预计这些研究将揭示出对神经源性胰腺炎发病机理至关重要的新途径。重要的是，这些结果可能会确定治疗人类急性胰腺炎的新型治疗靶标。