Complement Convertase: Assembly, Function and Regulation

描述（由申请人提供）：补体标记感染因子进行免疫清除或溶解，促进局部炎症反应，促进B细胞活化和Ab产生。补体在细胞凋亡、繁殖和组织再生过程中也很活跃，尽管其在这些情况下的生物学意义尚不清楚。在消极方面，补体是人类疾病中组织损伤的主要原因。虽然有一些第一代补体抑制剂正在进行临床试验，但仍迫切需要用于临床使用的新型补体基试剂。C3转化酶是补体活化的主要酶。补体相关疾病和损伤可追溯至不适当的转换酶组装（如自身免疫）和转换酶调节功能障碍（如非典型溶血性尿毒综合征，年龄相关性黄斑变性）。控制转化酶的激活和调节是预防补体相关损伤和促进补体对病原体、肿瘤和其他适当靶点的活性的治疗策略的关键。我们的长期目标是根据从C3转换研究中获得的理解设计新的临床方法。我们已经发现properdin直接结合到某些微生物表面，在那里它启动转化酶组装和补体激活。这些发现特别说明了properdin在宿主防御奈瑟菌感染中的关键作用，表明properdin可能在识别其他微生物靶标中发挥重要作用，并支持了一种补体激活模型，其中properdin发挥的作用比目前认为的要突出得多。我们也有证据表明，适当蛋白导向的补体激活在程序性清除不良细胞（凋亡）中起作用。我们相信，对propertin导向的补体激活的深入研究将导致对补体激活在免疫和细胞和组织水平的内务功能中的机制和范围的新理解，并将导致新的治疗靶点和策略来抑制和指导补体依赖性破坏。为此，我们提出针对以下具体目标的实验：阐明特异蛋白导向补体活化的动力学和机制。2. 表征对有核细胞和病原体的“属性标记”的影响。3. 定义在目标识别中决定正确的结构元素。

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.