NEURAL REGULATION OF PANCREATIC FUNCTION

胰腺功能的神经调节

• 批准号: 6176209
• 负责人: Kimberly Saunders Kirkwood
• 金额: $ 13.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-15 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6176209
• 关键词: confocal scanning microscopy; dosage; endopeptidases; gastrointestinal function; gastrointestinal pharmacology; genetically modified animals; histology; immunocytochemistry; inflammation; laboratory mouse; myeloperoxidase; neuropeptide receptor; neuroregulation; neutrophil; pancreas; pancreatitis; stainings; tachykinin

DESCRIPTION (Adapted from Applicant's Abstract): Approximately 10% of patients with acute pancreatitis die from uncontrolled pancreatic inflammation that results in massive fluid losses and shock. The regulation of pancreatic inflammation is poorly understood. In the trachea, sensory nerves regulate inflammation by releasing tachykinins that bind to endothelial cells and induce arteriolar vasodilatation, plasma extravasation and neutrophil infiltration. This well-characterized phenomenon is called neurogenic inflammation. The general hypothesis of this proposal is that neurogenic mechanisms are essential to the pathogenesis of acute pancreatitis. Specifically, we hypothesize that a) tachykinins induce plasma extravasation and neutrophil infiltration in the pancreas by interacting with neurokinin receptors, b) the pro-inflammatory effects of tachykinins are terminated by cell surface peptidases, and c) tachykinins and their receptors regulate inflammation in a widely-used model of acute pancreatitis. Due to the recent availability of "knockout" mice in which the genes encoding neurokinin receptors or cell surface peptidases have been deleted by homologous recombination, these experiments will be performed in mice. Pancreatic inflammation will be assessed by 1) quantifying and localizing plasma extravasation using Evans blue and Monastral blue, respectively, 2) identifying and measuring endothelial cell gaps through which plasma extravasates using a silver stain and light microscopy, 3) quantifying and localizing neutrophil infiltration using myeloperoxidase, and 4) defining the extent of edema, and cytoplasmic vacuolization using histological criteria. Specific Aim 1 will define the contribution of exogenous and endogenous tachykinins to the initiation of acute pancreatic inflammation. The time-course and dose-response will be determined, and the neurokinin receptors that mediate these effects will be identified using antagonists and knockout mice, and localized using receptor-specific antisera. Specific Aim 2 will examine the role of peptidases in the termination of tachykinin-induced pancreatic inflammation. The peptidases neutral endopeptidase and angiotensin converting enzyme will be localized in the pancreas using specific antisera, and their importance in tachykinin-induced inflammation will be determined using inhibitors and knockout mice. Specific Aim 3 will define the importance of sensory nerves, and specifically tachykinins, in the pathogenesis of acute pancreatitis. Using neurokinin receptor antagonists, peptidase inhibitors, and knockout mice, we will delineate the neurogenic mechanisms that regulate inflammation in acute pancreatitis.

描述（根据申请人的摘要改编）：大约10％ 急性胰腺炎患者死于不受控制的胰腺 炎症会导致巨大的液体损失和冲击。 法规 胰腺炎症的理解很少。 在气管中，感觉 神经通过释放与 内皮细胞并诱导小动脉血管扩张，血浆外渗 和中性粒细胞浸润。 这种特殊的现象称为 神经源性炎症。 该提议的一般假设是 神经源机制对于急性发病机理至关重要 胰腺炎。 具体而言，我们假设a）速素诱导 血浆渗出和胰腺中性粒细胞浸润 与神经运动素受体相互作用，b） 旋转金蛋白被细胞表面肽酶终止，c）旋转金蛋白 他们的受体在广泛使用的急性模型中调节炎症 胰腺炎。 由于最近有“淘汰”小鼠的可用性 编码神经运动素受体或细胞表面肽酶的基因已经 通过同源重组删除，这些实验将在 老鼠。 胰腺炎症将通过1）量化和 使用Evans Blue和Monastral Blue定位血浆渗出， 2）通过识别和测量通过 血浆使用银色染色和光学显微镜进行外出奢华，3） 使用髓过氧化物酶量化和定位嗜中性粒细胞浸润， 4）使用使用水肿的程度和细胞质液泡来使用 组织学标准。 具体目标1将定义 外源性和内源性速素开始急性胰腺 炎。 时间课和剂量反应将确定，并 将使用介导这些作用的神经激素受体使用 拮抗剂和敲除小鼠，并使用受体特异 安排。 具体目标2将检查肽酶在 旋转金蛋白诱导的胰腺炎症的终止。 肽酶 中性内肽酶和血管紧张素转化酶将定位于 使用特定抗血清的胰腺及其在 旋转金蛋白诱导的炎症将使用抑制剂和 淘汰老鼠。 特定目标3将定义感官神经的重要性， 以及急性胰腺炎的发病机理。 使用神经运动素受体拮抗剂，肽酶抑制剂和敲除 小鼠，我们将描述调节炎症的神经源机制 在急性胰腺炎中。