Complement Anaphylatoxin Receptors in Inflammation

描述(由申请人提供)：主要的生物后果之一 补体激活的关键是产生三个小的阳离子多肽 C3a、C4a和C5a统称为补体过敏性毒素。这个 补体过敏性毒素是一种强大的促炎分子，它能介导 与七种跨膜G蛋白结合的多种生物学功能 表达在特定靶细胞上的偶联受体。急慢性疾病 补体过敏性毒素多肽的过度生产被认为是主要的 多种疾病的致病因素，包括类风湿 关节炎、牛皮癣、感染性休克、心肌缺血损伤、急性 呼吸窘迫综合征和多系统器官衰竭。的目标是 这项研究计划是为了增加我们对具体和 补充过敏性毒素多肽及其受体的整体作用 在炎症和免疫力方面。在接下来的几年里，蜂窝 C3a受体介导的表达和生物学功能将是 仔细检查了一下。此外，C3a在体内的生物学作用 将使用C3a受体“敲除”小鼠来研究和评估受体 在几种具有良好特征的炎症、感染和 自身免疫力。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过敏性毒素受体及其介导的生物学研究 表达C3a受体的细胞的功能，2)确定 C3a受体缺陷在已建立的大鼠肺部炎症中的作用 免疫复合体损伤、哮喘、细菌感染和清除，3)至 用ESTABLISE测定皮肤中C3a受体缺陷的影响 感染性皮炎、免疫复合体损伤和大疱性类天疱疮的模型， 4)测定腹膜C3a受体缺陷的影响 使用已建立的免疫复合型腹膜炎、急性脓毒症模型 腹膜炎和感染性休克。

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.