COMPLEMENT CONVERTASE: ASSEMBLY, FUNCTION AND REGULATION

补充转化酶：组装、功能和调节

• 批准号: 8437634
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437634
• 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; 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. PUBLIC HEALTH RELEVANCE: The complement proteins protect us from infectious microorganisms but under other circumstances they can cause severe and potentially life-threatening tissue damage. The proposed research will provide new strategies and tools for successful therapeutic intervention in such cases.

描述（由申请人提供）：补体替代激活途径（AP）是人类疾病和损伤状态中组织损伤的主要原因。旨在抑制有害补体活性的治疗药物已开始在临床环境中出现。 C3 转化酶是补体激活的关键酶。补体相关疾病和损伤可以追溯到转化酶组装不当（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）。转化酶组装和调节的控制是预防补体相关损伤的治疗策略的关键。我们的长期目标是设计预防或抑制有害补体的新方法。 在三种补体激活途径中，旁路途径（AP）尤其与多种疾病和损伤状态有关。该提案针对 AP，特别是备解素，备解素是 AP 转化酶特有的成分，其功能尚未完全了解。最近，我们和其他人使用动物模型系统来证明备解素是改善 AP 依赖性发病机制的有前途的治疗靶点。为了了解备解素功能的机制基础并开发基于备解素的治疗性抑制 AP 依赖性补体活性的策略，我们提出以下具体目标： 具体目标 1. 使用体外模型系统来表征备解素模式识别活性对 C 激活的贡献。具体目标 2. 阐明备解素在 AP 依赖性发病机制动物模型中的作用。具体目标 3. 开发抗备解素试剂，用于治疗性抑制病理性 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，并对旨在控制补体旁路途径的治疗策略产生重大影响。 公共健康相关性：补体蛋白可以保护我们免受传染性微生物的侵害，但在其他情况下，它们可能会导致严重且可能危及生命的组织损伤。拟议的研究将为此类病例的成功治疗干预提供新的策略和工具。