Complement Anaphylatoxin Receptors in Inflammation

描述（由申请人提供）：补体激活的主要生物学后果之一是产生三种小阳离子肽C3 a、C4 a和C5 a，统称为补体过敏毒素。补体过敏毒素通过与特异性靶细胞上表达的七种跨膜G蛋白偶联受体结合来介导多种生物学功能。两种最有效的过敏毒素C3 a和C5 a的急性和慢性过度产生被认为是许多疾病的发病机制的主要贡献者，包括类风湿性关节炎、脓毒症、组织缺血性损伤、急性呼吸窘迫综合征、多系统器官衰竭和特应性哮喘。补体过敏毒素由羧肽酶调节，羧肽酶产生活性低得多的desArg衍生物C3 adesArg和C5 adesArg。历史上，CPN，在血浆中组成型表达的羧肽酶，被认为是补体过敏毒素的唯一羧肽酶调节剂。最近，另外两种分别在血清和上皮细胞（肺和肾）上表达的羧肽酶CPR和CPM已被提出作为C3 a和C5 a的另外的羧肽酶调节剂。在过去的几年中，我们实验室以及其他实验室的研究表明，补体过敏毒素C3 a和C5 a除了其传统的炎性特性外，还是过敏性和感染性疾病中CD 4 + Th 1和Th 2效应功能的重要调节剂。本研究计划的目标是增加我们对补体过敏毒素及其受体在相关感染性疾病中介导炎症，免疫和T细胞反应的调节和生物学功能的理解。通过使用我们实验室中产生的C3 aR、C5 aR、CPN和CPM“敲除”小鼠，我们提出了主要目标：1）描述和评价CPN、CPR和CPM在调节由C3 a、C5 a、缓激肽和其它重要炎性分子介导的生物反应中的总体生理学意义，和2）描述补体过敏毒素受体，C3 aR和C5 aR/CD 88调节T细胞效应功能，这在单核细胞增生李斯特菌的发病机制中是重要的。

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 mediate numerous biological functions by binding to seven transmembrane G-protein coupled receptors expressed on specific target cells. The acute and chronic overproduction of the two most potent anaphylatoxins, C3a and C5a, is considered to be a major contributor to the pathogenesis of numerous diseases, including rheumatoid arthritis, sepsis, tissue ischemic injury, acute respiratory distress syndrome, multiple system organ failure, and atopic asthma. The complement anaphylatoxins are regulated by carboxypeptidases, which generate their much less active desArg derivatives, C3adesArg and C5adesArg. Historically, CPN, the carboxypeptidase expressed constitutively in plasma, was thought to be the sole carboxypeptidase regulator of complement anaphylatoxins. Recently, two other carboxypeptidases, CPR and CPM, which are expressed in the serum and on epithelial cells (lung and kidney), respectively, have been proposed as additional carboxypeptidase regulators of C3a and C5a. During the past few years studies in our laboratory as well as in others have revealed that the complement anaphylatoxins C3a and C5a in addition to their traditional phlogistic properties are significant modulators of CD4+ Th1 and Th2 effector functions in allergic and infectious disease. The goal of this research program is to increase our understanding of the regulation and biological functions that the complement anaphylatoxins and their receptors mediate in inflammation, immunity, and T cell responses in relevant infectious diseases. By employing C3aR, C5aR, CPN, and CPM "knock-out" mice generated in our laboratory, we propose to major goals: 1) to delineate and evaluate the overall physiological significance of CPN, CPR, and CPM in regulating biological responses mediated by C3a, C5a, bradykinin, and other important inflammatory molecules, and 2) delineate cellular interactions and molecular mechanisms by which the complement anaphylatoxin receptors, C3aR and C5aR/CD88 modulate T-cell effector functions, which are important in the pathogenesis of Listeria monocytogenes.