Complement Anaphylatoxin Receptors in Inflammation

补充炎症中的过敏毒素受体

• 批准号: 6699403
• 负责人: RICK A. WETSEL
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6699403
• 关键词: anaphylatoxins; complement; complement deficiency; complement receptor; cytokine; dermatitis; flow cytometry; genetically modified animals; immune complex diseases; immunofluorescence technique; inflammation; laboratory mouse; molecular pathology; pemphigus; peritonitis; polymerase chain reaction; receptor expression; septic shock; tissue /cell culture

DESCRIPTION (provided by applicant): One of the major biological consequences of complement activation is the generation of three small cationic peptides C3a, C4a, and C5a, collectively referred to as complement anaphylatoxins. The complement anaphylatoxins are potent proinflammatory molecules that mediate numerous biological functions by binding to seven transmembrane G-protein coupled receptors expressed on specific target cells. The acute and chronic overproduction of complement anaphylatoxin peptides is considered to be a major contributor to the pathogenesis of numerous diseases, including rheumatoid arthritis, psoriasis, septic shock, myocardial ischemic injury, acute respiratory distress syndrome, and multiple system organ failure. The goal of this research program is to increase our understanding of the specific and overall roles that complement anaphylatoxin peptides and their receptors play in inflammation and immunity. During the next several years, the cellular expression and biological functions mediated by the C3a receptor will be examined in detail. In addition, the in vivo biological role of the C3a receptor will be studied and evaluated using a C3a receptor "knock-out" mouse in several well-characterized models of inflammation, infection, and autoimmunity. These studies will be accomplished by four major specific aims: 1) to determine the cells in peripheral blood and selected tissues that express the C3a anaphylatoxin receptor, and to delineate C3a mediated biological functions by cells expressing the C3a receptor, 2) to determine the effect of C3a receptor deficiency on pulmonary inflammation in established models of immune-complex injury, asthma, and bacterial infection and clearance, 3) to determine the effect of C3a receptor deficiency in the skin using established models of infectious dermatitis, immune-complex injury, and bullous pemphigoid, and 4) to determine the effect of C3a receptor deficiency in the peritoneum using established models of immune-complex peritonitis, acute septic peritonitis, and septic shock.

描述（由申请人提供）：主要生物学后果之一 补体激活的过程是产生三个小阳离子肽 C3a、C4a和C5a，统称为补体过敏毒素。这 补体过敏毒素是有效的促炎分子，可介导 通过与七个跨膜 G 蛋白结合而发挥多种生物学功能 在特定靶细胞上表达的偶联受体。急性和慢性 补体过敏毒素肽的过量产生被认为是主要的 导致许多疾病的发病机制，包括类风湿病 关节炎、牛皮癣、感染性休克、心肌缺血性损伤、急性 呼吸窘迫综合征和多系统器官衰竭。目标是 这个研究计划是为了增加我们对具体和 补充过敏毒素肽及其受体的总体作用 在炎症和免疫方面。在接下来的几年里，蜂窝 C3a受体介导的表达和生物学功能 详细检查了。此外，C3a 的体内生物学作用 将使用 C3a 受体“敲除”小鼠来研究和评估受体 在几种明确表征的炎症、感染和 自身免疫。这些研究将通过四个主要具体目标来完成： 1) 确定外周血和选定组织中表达的细胞 C3a 过敏毒素受体，并描述 C3a 介导的生物 通过表达 C3a 受体的细胞发挥功能，2) 确定 C3a 受体缺乏对已建立的模型中肺部炎症的影响 免疫复合物损伤、哮喘、细菌感染和清除，3) 使用已建立的方法确定皮肤中 C3a 受体缺陷的影响 传染性皮炎、免疫复合物损伤和大疱性类天疱疮模型， 4) 确定腹膜中 C3a 受体缺陷的影响 使用已建立的免疫复合物腹膜炎、急性脓毒症模型 腹膜炎和感染性休克。