COMPLEMENT CONVERTASE: ASSEMBLY, FUNCTION AND REGULATION

补充转化酶：组装、功能和调节

• 批准号: 8897952
• 负责人: DENNIS EMIL HOURCADE
• 金额: $ 30.69万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897952
• 关键词: Active Sites; Acute; Affinity; Age related macular degeneration; Alternative Complement Pathway; Animal Model; Antibodies; Arthritis; Asthma; Autoimmune Process; Autoimmunity; B-Cell Activation; Binding; Biological; Biological Models; Chronic; Clinical; Complement; Complement 3 Convertase; Complement Activation; Cytolysis; Discrimination; Disease; Enzymes; Failure; Functional disorder; Goals; Health; Hemolytic-Uremic Syndrome; In Vitro; Infectious Agent; Inflammatory Response; Injury; Laboratories; Lead; Life; Lung; Modeling; Pathogenesis; Pathologic; Pathway interactions; Pattern Recognition; Peptides; Plasma; Prevention; Prevention approach; Prevention strategy; Production; Properdin; Reaction; Reagent; Regulation; Research; Role; Site; Source; Surface; System; Technology; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Work; base; design; human disease; immune clearance; in vitro Assay; in vitro Model; in vivo; inhibitor/antagonist; microbial; microorganism; mouse model; neutrophil; novel; novel strategies; peptidomimetics; polyanion; prototype; response; small molecule; success; therapeutic target; tool

DESCRIPTION (provided by applicant): The complement alternative activation pathway (AP) is a principal cause of tissue damage in human diseases and injury states. Therapeutic agents designed to inhibit harmful complement activity have begun to emerge in the clinical setting. The C3 convertases are the key 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 assembly and regulation is the key to therapeutic strategies for prevention of complement-related damage. Our long-range goal is to design new approaches for the prevention or inhibition of harmful complement. Of the three complement activation pathways, the alternative pathway (AP) in particular has been implicated in numerous disease and injury states. This proposal is directed to the AP and specifically to properdin, a component unique to the AP convertases and whose functions are not yet fully understood. Recently we, and others, have employed animal model systems to demonstrate that properdin is a promising therapeutic target for the amelioration of AP-dependent pathogenesis. In order to understand the mechanistic basis of properdin function and to develop a properdin-based strategy for the therapeutic inhibition of AP- dependent complement activity, we propose the following SPECIFIC AIMS: Specific Aim 1. Use in vitro model systems to characterize the contribution of properdin pattern recognition activity to C activation. Specific Aim 2. Elucidate the role(s) of properdin in animal models of AP-dependent pathogenesis. Specific Aim 3. Develop anti-properdin reagents for the therapeutic inhibition of pathologic AP-dependent C activity. We expect the results from this work to have the potential to be highly translational and to significantly impact therapeutic strategies aimed at controlling the complement alternative pathway.

描述（由申请人提供）：补体替代激活途径（AP）是人类疾病和伤害状态组织损害的主要原因。旨在抑制有害补体活性的治疗剂在临床环境中已经开始出现。 C3转化酶是补体激活的关键酶。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）。转化酶组装和调节的控制是预防与补体损害的治疗策略的关键。我们的远程目标是为预防或抑制有害补体设计新方法。 在三种补体激活途径中，尤其是替代途径（AP）与许多疾病和损伤状态有关。该提案专门针对AP，这是AP转换酶独有的组成部分，其功能尚未完全理解。最近，我们和其他人采用了动物模型系统来证明适当的丁丁是改善AP依赖性发病机理的有希望的治疗靶标。为了了解适当丁丁功能的机理基础，并制定了基于适当的抑制APERIDENT ACTION活动的策略，我们提出了以下特定目的：特定目标1。使用体外模型系统来表征适当的模式识别活动对C激活的贡献。具体目的2。阐明了适当的发病机理动物模型中适当的作用。具体目的3。开发抗磷脂试剂，以抑制病理AP依赖性C活性。我们期望这项工作的结果具有高度转化的潜力，并会显着影响旨在控制补体替代途径的治疗策略。