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.

补充是一种体液先天免疫系统，在宿主防御和桥接中起着重要作用自适应免疫。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激活；其中之一是通过胶原蛋白途径（LP）触发的胶原蛋白途径（LP）分子（PRM）。 PRM与微生物或改变的自我组织结合后，特定于激活称为MASP的蛋白酶。激活masps是LP补充的关键步骤激活以及随之而来的宿主防御反应或组织损伤后果。作用机理体内的assp尚未得到充分了解，最近的研究揭示了令人惊讶的联系 MASP3和替代途径（AP）补体激活。已经表明masp3扮演在将促因子D（FD）转换为成熟的活动FD中的重要作用。该提案的目标是两个折， 1）了解MASP2和MASP3是否在补体介导的病理中起重要作用，并且如果是这样，是否针对这些酶代表了可行的治疗方法。 2）了解如何 FD活性通过MASP3和推定的丝氨酸蛋白酶抑制剂在体内调节。为此，我们提出该项目的三个特定目标。特定的目标1。使用MASP2 KO小鼠并堵塞mAb并测试角色补体介导的疾病中的MASP2和LP。特定目标2。使用MASP3 KO小鼠并阻塞 mAbs并测试MASP3在调节AP补体活动中的作用，并作为AP中的治疗靶标补体依赖性疾病。特定目的3。检验以下假设，即MASP3对Pro-FD的成熟不是默认反应，而是一个受调节的过程，而是构成不受监管的成熟FD活动通过因子B裂解导致AP补体消耗，该因子可以通过治疗剥削。这些研究将为靶向MASP2和MASP3提供概念证明，并添加新关于FD和AP补体活动的基本知识在体内受到调节。