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（由申请人提供）：补体标记具有免疫清除或裂解的传染剂，促进局部炎症反应，并促进B细胞激活和AB产生。在凋亡，繁殖和组织再生过程中，补体在这些情况下作用的生物学意义尚不清楚。在负面，补体是人类疾病组织损害的主要原因。虽然有几种接受临床试验的第一代补体抑制剂，但仍需要新颖的基于补体的试剂以供临床使用。 C3转化酶是补体激活的主要酶。可以追溯到与补体相关疾病和损伤，既可以追溯到不适当的转化酶组件（例如自身免疫性），又可以转化酶调节剂功能障碍（例如非典型HUS，与年龄相关的黄斑变性）。转化酶激活和调节的控制是预防补体损害的治疗策略的关键，以及促进对病原体，肿瘤和其他适当靶标的补体活动。我们的远程目标是根据对C3转化酶的研究获得的理解来设计新的临床方法。我们已经发现，适当的丁丁直接与某些微生物表面结合，在该表面启动转化酶的组装和补体激活。这些发现特别说明了适当丁丁在宿主防御奈瑟氏菌感染中的关键作用，这表明Prowerdin可能在鉴定其他微生物靶标的识别中起主要作用，并支持一种补体激活模型，在这种补充激活中，适当的丁丁在当前思维中起着比反射性更重要的作用。我们还获得了证据表明，正确的指导补体激活在编程的不良细胞（凋亡）中起作用。我们认为，对适当指导的补体激活进行了深入的检查将导致对免疫，细胞和组织水平的家政功能中补体激活的机制和范围的新理解，并将导致新颖的治疗靶标和策略，以抑制抑制和相互依赖的销毁。为此，我们提出了针对以下特定目的的实验：1。阐明适当的指导补体激活的动力学和机制。 2。表征“正确的标记”对成核细胞和病原体的影响。 3。定义确定目标识别中适当的结构元素。