Complement Convertase: Assembly, Function and Regulation

补体转化酶：组装、功能和调节

• 批准号: 7800882
• 负责人: DENNIS EMIL HOURCADE
• 金额: $ 25.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7800882
• 关键词: Accounting; Age related macular degeneration; Apoptosis; Apoptotic; Autoimmunity; B-Cell Activation; Binding; Biological; Biological Assay; Biosensor; Cell Line; Cells; Clinical; Clinical Trials; Complement; Complement 3 Convertase; Complement Activation; Complement Inactivators; Cytolysis; Discrimination; Disease; Elements; Enzymes; Excision; Functional disorder; Generations; Goals; Host Defense; Housekeeping; Immunity; Infection; Infectious Agent; Inflammatory Response; Injury; Kinetics; Lead; Liver Regeneration; Methods; Modeling; Neisseria; Play; Prevention; Production; Properdin; Reagent; Regulation; Reproduction; Research Personnel; Role; Side; Sperm-Ovum Interactions; Surface; Surface Plasmon Resonance; T-Lymphocyte; Therapeutic; Therapeutic Agents; Thinking; Tissues; alternative pathway complement C3 convertase; base; design; human disease; immune clearance; microbial; new therapeutic target; novel; novel strategies; pathogen; programs; research study; tissue regeneration; tumor

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.

描述（由申请方提供）：补体标记用于免疫清除或溶解的感染因子，促进局部炎症反应，并促进B细胞活化和Ab产生。补体在细胞凋亡、生殖和组织再生过程中也是活跃的，尽管其在这些情况下的作用的生物学意义尚不清楚。在负面方面，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，但仍然迫切需要用于临床用途的新型补体基试剂。C3转化酶是补体激活的主要酶。补体相关疾病和损伤可追溯至不适当的转化酶组装（例如自身免疫）和转化酶调节功能障碍（例如非典型HUS、年龄相关性黄斑变性）。转化酶活化和调节的控制是预防补体相关损伤和促进补体对病原体、肿瘤和其他适当靶标的活性的治疗策略的关键。我们的长期目标是根据对C3转化酶研究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，在那里它启动转化酶组装和补体激活。这些发现特别说明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中起主要作用，并支持补体激活模型，其中备解素发挥的作用比目前的想法更为突出。我们还获得了备解素导向的补体激活在程序性去除不需要的细胞（凋亡）中起作用的证据。我们相信，对备解素介导的补体激活的深入研究将导致对补体激活在免疫中以及在细胞和组织水平的管家功能中的机制和范围的新理解，并将导致用于抑制和指导补体依赖性破坏的新的治疗靶点和策略。为此，我们提出了针对以下具体目标的实验：1。阐明备解素介导的补体激活的动力学和机制。2.表征“备解素标记”对有核细胞和病原体的影响。3.定义决定备解素在靶点识别中的结构要素。