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。在某些情况下，补体激活也可以导致显著的自体 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； 其中之一是通过凝集素途径(LP)，该途径由胶原样可溶模式识别触发 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 一组被称为MASP的蛋白酶被激活。MASP的激活是Lp补体的关键步骤 激活和随之而来的宿主防御反应或组织损伤后果。其作用机制 体内的MASPs还没有被很好地理解，最近的研究揭示了一个惊人的联系 MASP3和替代途径(AP)补体激活。已有研究表明，MASP3在 在将原因子D(Fd)转化为成熟的活性Fd的过程中发挥重要作用。这项提议的目标有两个方面， 1)了解MASP2和MASP3是否在补体介导的病理中起重要作用，以及 如果是这样，靶向这些酶是否代表一种可行的治疗方法；以及2)了解如何 在体内，FD活性受MASP3和一种可能的丝氨酸蛋白酶抑制剂(S)的调节。为此，我们建议 这个项目的三个具体目标。具体目的1.用MASP2KO小鼠和阻断单抗并检测其作用 补体介导疾病中MASP2和LP的表达。特定目的2.利用MASP3KO小鼠并阻断 检测MASP3在调节AP补体活性中的作用及其作为AP治疗靶点的作用 补体依赖型疾病。特异目的3.验证MASP3对Fd前体成熟的假设 不是一种默认反应，而是一种受调控的过程，这种结构性的、不受调控的成熟FD活动 通过B因子的裂解导致AP补体的消耗，这可以用于治疗。这些 研究将为治疗靶向MASP2和MASP3提供概念证明，并增加新的 关于FD和AP补体活性如何在体内被调节的基础知识。