Pathogenic Mechanisms of Pancreatitis

胰腺炎的发病机制

基本信息

批准号：
7178470
负责人：
Rodger A. Liddle
金额：
$ 27.45万
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 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7178470
关键词：
Acinar Cell Acute Afferent Neurons Amino Acids Animals Biological Assay Capsaicin Categories Cells Clinical Complex Condition Data Development Disease Edema Enzyme Activation Esthesia Event Evolution Family Fiber Functional disorder Genetic Gland Goals Inflammation Inflammatory Inflammatory Response Kazal Pancreatic Trypsin Secretory Inhibitor Knockout Mice Leukocytes Ligands Link Measures Mediating Mediator of activation protein Morbidity - disease rate Mus Neurogenic Inflammation Neurons Neuropeptides Neurotransmitters Neutrophil Infiltration Nociception Numbers Pain Pancreas Pancreatic enzyme Pancreatitis Pathogenesis Positioning Attribute Process Proteolysis Receptor Activation Relative (related person)Resources Rodent Model Role Sensory Sensory Nerve Endings Severities Signal Transduction Spinal Ganglia Spinal cord posterior horn Stimulus Substance P Substance P Receptor Tachykinin Testing Tissues Transgenes Transgenic Mice Trypsin Ursidae Family Vascular Permeabilities Vasodilation Vasodilation disorder Viscera acute pancreatitis afferent nerve capsaicin receptor chronic pancreatitis cytokine design improved mortality mouse model nerve supply neuronal cell body novel pancreatic secretory trypsin inhibitor I receptor receptor internalization tool vanilloid receptor subtype 1

项目摘要

DESCRIPTION (provided by applicant): Pancreatitis can be a devastating clinical condition associated with considerable morbidity and mortality that is believed to result from premature activation of pancreatic enzymes within the parenchyma of the gland, leading to tissue autodigestion, subsequent inflammation, and ultimately tissue destruction. It is apparent that a number of complex and interrelated processes involving activation of pancreatic enzymes and inflammatory mediators participate in a cascade of events that produce pancreatitis. However, the precise pathogenic steps producing the final manifestations of the disease are not established. Neurogenic inflammation is a well established principle in some inflammatory conditions where neurotransmitters such as substance P are key mediators of pain sensation, neutrophil infiltration, edema, and local proteolysis. Mice deficient in the neurokinin-1 (NK-1) receptor have been shown to have less severe experimental pancreatitis compared to normal mice suggesting that substance P is important for the full inflammatory response. Recent studies by the PI and others have linked substance P release from primary sensory neurons to pancreatic inflammation and pancreatitis and suggest that primary sensory neuronal activation is an important upstream event in the development of pancreatitis. Primary afferent neurons are capsaicin-sensitive and express the capsaicin receptor [known as the vanilloid receptor-1 (VR1)]. The PI's preliminary pharmacological data indicate that VR1 inhibition reduces the severity of experimental pancreatitis. The current application is designed to test the hypothesis that primary sensory innervation is a necessary component of acute and chronic pancreatitis. The goal of this project is to define the upstream events from NK-1 receptor activation that initiate pancreatitis. These studies will utilize recently developed mouse models to examine the following Specific Aims: (1) To establish the critical role of VR1 in pancreatic inflammation and pancreatitis by determining if VR1 knock-out mice are protected against acute and/or chronic pancreatitis; (2) To determine if intrapancreatic trypsin inhibition, through the pancreatic specific expression of PSTI-I in transgenic mice, protects against pancreatitis through a VR1-mediated mechanism; (3) To characterize the endogenous ligands for the VR1 receptor responsible for mediating the inflammatory response in pancreatitis. These results should help both elucidate the importance of primary sensory innervation in the pathogenesis of pancreatitis and provide possible new strategies for the treatment of pancreatitis.

描述（由申请人提供）：胰腺炎可能是一种破坏性的临床病症，具有相当高的发病率和死亡率，据信这是由于腺体实质内胰酶过早激活造成的，导致组织自身消化、随后的炎症和最终的组织破坏。显然，涉及胰腺酶和炎症介质激活的许多复杂且相互关联的过程参与了产生胰腺炎的一系列事件。然而，产生该疾病最终表现的精确致病步骤尚未确定。神经源性炎症是某些炎症条件下的一个公认原理，其中 P 物质等神经递质是痛觉、中性粒细胞浸润、水肿和局部蛋白水解的关键介质。与正常小鼠相比，神经激肽-1 (NK-1) 受体缺陷的小鼠实验性胰腺炎的严重程度较轻，这表明 P 物质对于完整的炎症反应很重要。 PI 和其他人最近的研究将初级感觉神经元释放的 P 物质与胰腺炎症和胰腺炎联系起来，并表明初级感觉神经元激活是胰腺炎发展的重要上游事件。初级传入神经元对辣椒素敏感并表达辣椒素受体 [称为香草酸受体 1 (VR1)]。 PI 的初步药理学数据表明，VR1 抑制可降低实验性胰腺炎的严重程度。当前的应用程序旨在测试初级感觉神经支配是急性和慢性胰腺炎的必要组成部分的假设。该项目的目标是确定引发胰腺炎的 NK-1 受体激活的上游事件。这些研究将利用最近开发的小鼠模型来检查以下具体目标：（1）通过确定 VR1 敲除小鼠是否能够预防急性和/或慢性胰腺炎，确定 VR1 在胰腺炎症和胰腺炎中的关键作用； (2) 确定通过转基因小鼠中 PSTI-I 的胰腺特异性表达来抑制胰腺内胰蛋白酶是否可以通过 VR1 介导的机制预防胰腺炎； (3) 表征负责介导胰腺炎炎症反应的 VR1 受体的内源性配体。这些结果应有助于阐明初级感觉神经支配在胰腺炎发病机制中的重要性，并为胰腺炎的治疗提供可能的新策略。