MASPs as therapeutic targets in complement-mediated diseases

MASP 作为补体介导疾病的治疗靶点

• 批准号: 9973779
• 负责人: Wenchao Song
• 金额: $ 58.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-18 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973779
• 关键词: Alternative Complement Pathway; Antibodies; Area; Arthritis; Autoimmune Process; Autologous; Binding; Blood Proteins; Body part; Cell surface; Cleaved cell; Clinical; Clinical Data; Collagen; Collectins; Complement; Complement Activation; Complement Factor B; Complement Factor D; Complex; Consumption; Data; Development; Disease; Disease model; Enzymes; Goals; Hemolytic-Uremic Syndrome; Host Defense; IGA Glomerulonephritis; Immune system; Inflammatory; Innate Immune System; Kidney Diseases; Knockout Mice; Knowledge; Lead; Lectin; Link; MASP2 gene; Mannose Binding Lectin; Mediating; Medical; Microbe; Monoclonal Antibodies; Pathogenesis; Pathology; Pathway interactions; Pattern Recognition; Pharmaceutical Preparations; Plasma; Play; Process; Protein C Inhibitor; Proteins; Reaction; Regulation; Role; Serine Protease; Serine Proteinase Inhibitors; Testing; Therapeutic; Tissues; adaptive immunity; alternative pathway complement C3 convertase; base; complement pathway; defense response; enzyme pathway; ficolin; group-specific protease; in vivo; mannose-binding protein-associated serine proteases; microbial; mouse model; novel therapeutics; pre-clinical; prototype; sugar; theories; therapeutic target; tissue injury

Complement is a humoral innate immune system that plays an important role in host defense and in bridging adaptive immunity. Under certain conditions, complement activation can also cause significant autologous tissue injury leading to complement-mediated diseases. Complement is activated via three different pathways; one of which is by the lectin pathway (LP) which is triggered by collagen-like soluble pattern recognition molecules (PRMs). Upon binding of PRMs to sugar molecules on microbes or altered self-tissues, a specific group of proteases called MASPs are activated. Activation of MASPs is the key step in LP complement activation and the ensuing host defense response or tissue injury consequence. The mechanism of action of MASPs in vivo has not been well understood and recent studies have revealed a surprising link between MASP3 and the alternative pathway (AP) complement activation. It has been shown that MASP3 plays an essential role in converting pro-factor D (FD) to mature active FD. The objectives of this proposal are two fold, 1) to understand whether MASP2 and MASP3 play significant roles in complement-mediated pathologies, and if so, whether targeting these enzyme represents a feasible therapeutic approach; and 2) to understand how FD activity is regulated in vivo by MASP3 and a putative serine protease inhibitor(s). To this end, we propose three specific aims in this project. Specific aim 1. To use MASP2 KO mice and blocking mAbs and test the role of MASP2 and LP in complement-mediated diseases. Specific aim 2. To use MASP3 KO mice and blocking mAbs and test the role of MASP3 in regulating AP complement activity and as a therapeutic target in AP complement-dependent diseases. Specific aim 3. To test the hypothesis that maturation of pro-FD by MASP3 is not a default reaction, but rather a regulated process, and that constitutive, unregulated mature FD activity leads to AP complement consumption via Factor B cleavage which can be exploited therapeutically. These studies will provide proof of concept for therapeutically targeting MASP2 and MASP3, as well as add new fundamental knowledge on how FD and AP complement activity is regulated in vivo.

补体是一种体液先天免疫系统，在宿主防御和桥接中发挥重要作用 适应性免疫。在某些条件下，补体激活也会引起显着的自体 组织损伤导致补体介导的疾病。补体通过三种不同的途径被激活； 其中之一是凝集素途径 (LP)，该途径由类胶原蛋白可溶性模式识别触发 分子（PRM）。当 PRM 与微生物或改变的自身组织上的糖分子结合时，特定的 一组称为 MASP 的蛋白酶被激活。 MASPs的激活是LP补充的关键步骤 激活和随后的宿主防御反应或组织损伤后果。作用机制 体内 MASP 尚未得到充分了解，最近的研究揭示了 MASP 之间的惊人联系 MASP3 和旁路途径 (AP) 补体激活。事实证明，MASP3 发挥着 在将前因子 D (FD) 转化为成熟的活性 FD 过程中发挥着重要作用。该提案的目标有两个， 1) 了解 MASP2 和 MASP3 是否在补体介导的病理学中发挥重要作用，以及 如果是这样，针对这些酶是否代表一种可行的治疗方法； 2）了解如何 FD 活性在体内由 MASP3 和推定的丝氨酸蛋白酶抑制剂调节。为此，我们建议 该项目的三个具体目标。具体目的1.使用MASP2 KO小鼠和阻断mAb并测试作用 MASP2 和 LP 在补体介导的疾病中的作用。具体目标2.使用MASP3 KO小鼠并阻断 mAb 并测试 MASP3 在调节 AP 补体活性中的作用以及作为 AP 治疗靶点 补体依赖性疾病。具体目标 3. 检验 MASP3 使 pro-FD 成熟的假设 不是默认反应，而是一个受调控的过程，并且是本构的、不受调控的成熟 FD 活性 通过因子 B 裂解导致 AP 补体消耗，可用于治疗。这些 研究将为针对 MASP2 和 MASP3 的治疗提供概念证明，并添加新的 关于体内 FD 和 AP 补体活性如何调节的基础知识。