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MASPs as therapeutic targets in complement-mediated diseases

MASP 作为补体介导疾病的治疗靶点

基本信息

批准号：
10350607
负责人：
Wenchao Song
金额：
$ 58.19万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10350607
关键词：
Alternative Complement Pathway Antibodies Area Arthritis Autoimmune Autoimmune Diseases Autologous Binding Blood Proteins Body part Cell surface 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

项目摘要

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着重要作用适应性免疫在某些情况下，补体激活也可引起显著的自体免疫反应。组织损伤导致补体介导的疾病。补体通过三种不同的途径激活; 其中之一是通过凝集素途径（LP），其由胶原样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，一组称为MASP的蛋白酶被激活。MASPs的活化是LP补体激活的关键步骤。激活和随后的宿主防御反应或组织损伤后果。的作用机制体内MASPs尚未得到很好的理解，最近的研究揭示了MASPs与体内MASPs之间令人惊讶的联系。 MASP 3和旁路途径（AP）补体激活。已经表明，MASP 3起作用，在将前因子D（FD）转化为成熟活性FD中起重要作用。这项建议有两个目的， 1)了解MASP 2和MASP 3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，靶向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MASP 3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。具体目标1.为了使用MASP 2 KO小鼠和阻断mAb并测试MASP 2 KO小鼠和阻断mAb对MASP 2的作用， MASP 2和LP在补体介导的疾病中的作用。具体目标2。为了使用MASP 3 KO小鼠和阻断MASP 3基因， mAb和测试MASP 3在调节AP补体活性中的作用以及作为AP中的治疗靶标补体依赖性疾病具体目标3。为了检验通过MASP 3的pro-FD成熟不是默认反应，而是一个受调节的过程，并且组成性的、不受调节的成熟FD活性通过因子B裂解导致AP补体消耗，这可以在治疗上加以利用。这些研究将为靶向MASP 2和MASP 3的治疗提供概念证明，并增加新的关于FD和AP补体活性如何在体内调节的基础知识。