LPS-Peptide Interaction in Bladder Inflammation

LPS-肽在膀胱炎症中的相互作用

• 批准号: 6802572
• 负责人: RICARDO SABAN
• 金额: $ 8.89万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-29 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802572
• 关键词: LPS; Peptide; Interaction; Bladder; Inflammation

DESCRIPTION (provided by applicant): Substance P derived from sensory C fibers play a major role in bladder inflammation. We presented evidence of a mandatory role of mast cells and substance P receptors in cystitis. However, it is not clear how mast cell degranulation leads to activation of sensory nerves and SP release. Using classical animal models and cDNA array technology, we characterized a common pathway that, regardless of the initiating stimulus (LPS, antigen, or SF), is activated in cystitis. This pathway includes a receptor for mast cell tryptase (protease-activating receptors; PAR), and NF-kB genes. We further presented evidence indicating that NF-kB is involved in experimental cystitis and that treatment with a proteosome inhibitor (lactacystin) or phosphodiestase 4 inhibitor (rolipram) blocks both the expression of NF-kB genes and inflammation. The central hypothesis of this proposal is that regardless of the stimulus (LPS, mast cell tryptase, or antigen-challenge of sensitized animals), bladder inflammatory responses follow a common pathway which involves:activation of mast cells, tryptase release, activation of PAR on blood vessels and sensory nerves, release of SP, activation of NK receptors, translocation of NF-kB, and translation of inflammatory genes. Therefore, therapeutic interventions to control mast cell degranulation, PAR activation, NK1 receptors activity, or NF-kB will alter the outcome and severity of cystitis. We propose to study three well-characterized models of bladder inflammation (antigen, tryptase, and LPS) in which mast cells, protease-activating receptors, and! or SP receptors have been implicated as biological modulators of the inflammatory response. The degree of bladder inflammation will be determined by a well-established morphometric analysis and cDNA arrays. Results will be confirmed by RNase protection assays and cellular patterns of expression will be performed by in situ hybridization and immunohistochemistry. Aim 1 will determine whether protease-activating receptors (PARs) play a central role in cystitis and Aim 2 will determine whether NE-kB translates the stimulus into inflammatory gene regulation. These studies will identify and define the important mechanisms involved in bladder inflammation and provide new insights for developing treatment strategies for cystitis.

描述（由申请人提供）：来源于感觉C纤维的P物质在膀胱炎症中起主要作用。我们提出了肥大细胞和P物质受体在膀胱炎中的强制性作用的证据。然而，目前尚不清楚肥大细胞脱粒如何导致感觉神经激活和SP释放。使用经典的动物模型和cDNA阵列技术，我们的特点是一个共同的途径，无论起始刺激（LPS，抗原，或SF），在膀胱炎中被激活。该途径包括肥大细胞类胰蛋白酶受体（蛋白酶激活受体; PAR）和NF-κ B基因。我们进一步提出的证据表明，NF-kB参与实验性膀胱炎和蛋白酶体抑制剂（lactacystin）或磷酸二酯酶4抑制剂（咯利普兰）的治疗阻断NF-kB基因的表达和炎症。该建议的中心假设是，无论刺激（LPS、肥大细胞类胰蛋白酶或致敏动物的抗原激发）如何，膀胱炎性反应遵循共同的途径，其涉及：肥大细胞活化、类胰蛋白酶释放、血管和感觉神经上的PAR活化、SP释放、NK受体活化、NF-κ B易位和炎性基因翻译。因此，控制肥大细胞脱颗粒、PAR活化、NK 1受体活性或NF-kB的治疗干预将改变膀胱炎的结局和严重程度。我们建议研究三种特征良好的膀胱炎症模型（抗原，类胰蛋白酶和LPS），其中肥大细胞，蛋白酶激活受体，和！或SP受体已被认为是炎症反应的生物调节剂。膀胱炎症的程度将通过完善的形态测定分析和cDNA阵列来确定。将通过RNA酶保护试验确认结果，并通过原位杂交和免疫组织化学进行细胞表达模式。目的1将确定蛋白酶激活受体（PARs）是否在膀胱炎中发挥核心作用，目的2将确定NE-kB是否将刺激转化为炎症基因调控。这些研究将确定和定义膀胱炎症的重要机制，并为制定膀胱炎的治疗策略提供新的见解。