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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：
10579828
负责人：
Wenchao Song
金额：
$ 57.38万
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/10579828
关键词：
Alternative Complement Pathway Antibodies Area Arthritis 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 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 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.

补体是一种体液性先天免疫系统，在宿主防御和桥接中起重要作用