Complement Convertase: Assembly, Function and Regulation

描述(申请人提供)：补体标记感染性物质以清除或溶解免疫，促进局部炎症反应，并促进B细胞活化和抗体的产生。补体在细胞凋亡、繁殖和组织再生过程中也是活跃的，尽管它在这些病例中的作用的生物学意义尚不清楚。从负面来看，补体是人类疾病中组织损伤的主要原因。虽然有几种第一代补体抑制剂正在进行临床试验，但临床上仍然迫切需要新的补体试剂。补体C3转换酶是补体激活的主要酶。补体相关的疾病和损伤可以追溯到转换酶装配不当(例如自身免疫)和转换酶调节功能障碍(例如非典型HUS、老年性黄斑变性)。控制转换酶的激活和调节是预防补体相关损伤和促进补体针对病原体、肿瘤和其他适当靶点的活性的治疗策略的关键。我们的长期目标是基于对C3转换酶的研究获得的理解，设计新的临床方法。我们已经发现，备解素直接结合到某些微生物表面，在那里它启动转换酶组装和补体激活。这些发现特别说明了备解素在宿主防御奈瑟氏菌感染中的关键作用，表明备解素可能在识别其他微生物靶标方面发挥重要作用，并支持补体激活模型，在该模型中，备解素发挥的作用比目前所反映的要突出得多。我们还获得了证据表明，备解素引导的补体激活在程序性去除不想要的细胞(细胞凋亡)中发挥作用。我们相信，对备解素诱导的补体激活的深入研究将导致对补体激活在免疫以及细胞和组织水平的管家功能中的机制和范围的新的理解，并将导致抑制和指导补体依赖破坏的新的治疗靶点和策略。为此，我们提出了针对以下特定目标的实验：1.阐明备解素诱导的补体激活的动力学和机制。2.描述“备解素标记”对有核细胞和病原体的影响。3.定义在目标识别中决定备解素的结构元素。

DESCRIPTION (provided by applicant): Complement marks infectious agents for immune clearance or lysis, promotes the local inflammatory response, and facilitates B cell activation and Ab production. Complement is also active during apoptosis, reproduction, and tissue regeneration although the biological significance of its roles in these cases is unclear. On the negative side, complement is a principal cause of tissue damage in human diseases. While there are several first-generation complement inhibitors undergoing clinical trials, there remains a compelling need for novel complement-based reagents for clinical use. The C3 convertases are the primary enzymes of complement activation. Complement-related disease and injury can be traced both to inappropriate convertase assembly (e.g. autoimmunity), and to convertase regulator dysfunction (e.g. atypical HUS, age-related macular degeneration). The control of convertase activation and regulation is the key to therapeutic strategies for both the prevention of complement-related damage, and the promotion of complement activity towards pathogens, tumors, and other appropriate targets. Our long-range goals are to design new clinical approaches based on an understanding gained from studies of the C3 convertases. We have discovered that properdin binds directly to certain microbial surfaces where it initiates convertase assembly and complement activation. These findings specifically account for the critical role of properdin in the host defense against Neisseria infection, suggest that properdin likely plays a major role in the identification of other microbial targets, and support a model of complement activation in which properdin plays a much more prominent role than reflected in current thinking. We have also obtained evidence that properdin-directed complement activation plays a role in the programmed removal of undesirable cells (apoptosis). We believe that an intense examination of properdin-directed complement activation will lead to a new understanding of the mechanism and scope of complement activation in immunity and in cell and tissue-level housekeeping functions, and will result in novel therapeutic targets and strategies for the suppression and the guidance of complement-dependent destruction. To that end we propose experiments directed to the following specific aims: 1. Elucidate the kinetics and mechanism of properdin-directed complement activation. 2. Characterize the impact of "properdin-tagging" on nucleated cells and pathogens. 3. Define the structural elements that determine properdin in target recognition.