Complement and allergic asthma

补体和过敏性哮喘

基本信息

批准号：
8617220
负责人：
Wenchao Song
金额：
$ 20万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-12 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8617220
关键词：
Adrenal Cortex Hormones Agonist Allergens Allergic Alternative Complement Pathway Anaphylatoxins Animal Model Apoptotic Arthritis Ascaridil Asthma Binding Breathing Cells Complement Complement Activation Developed Countries Developing Countries Development Disease Extrinsic asthma Fetal Death Figs - dietary Generations Genetic Genetic Models Glycoproteins Health Services Host Defense Human Immune response Immune system In Vitro Incidence Infection Inflammation Mediators Inflammatory Injury K/BxN model Knockout Mice Lectin Lytic Mediating Mediator of activation protein Modeling Mus Pathogenesis Pathway interactions Pattern Recognition Pharmaceutical Preparations Phase Pilot Projects Plasma Play Pneumonia Population Prevalence Properdin Proteins Public Health Reagent Role Serum Surface Testing Therapeutic Tissues Transgenic Mice Work adaptive immunity airway hyperresponsiveness airway inflammation alternative pathway complement C3 convertase complement system disease phenotype novel therapeutic intervention novel therapeutics pathogen prevent public health relevance receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Allergic asthma is a major public health problem that has increased markedly in prevalence in the past two decades. Due to insufficient understanding of its pathogenic mechanisms, the current treatments of asthma such as administration of systemic corticosteroids and inhaled beta agonists are far from optimal and there is a need for novel therapeutic approaches to be developed. One of the potential new targets for asthma therapy is the complement system. The focus of this R21 application is to explore the role of the complement protein properdin in the pathogenesis of asthma and the feasibility of its therapeutic targeting in this disease. Properdin is a plasma glycoprotein and th only known positive regulator of the complement cascade. It facilitates alternative pathway (AP) complement activation by stabilizing the C3 convertase C3bBb. Recent evidence has shown that properdin may also work as a pattern recognition molecule to bind to selective target surfaces and initiate AP complement activation. Moreover, in several AP complement-mediated tissue injury models including K/BxN arthritis, we have found that properdin contributed to disease pathogenesis. The overall objective of this application is to test the hypothesis that properdin is involved in the pathogenesis of allergic asthma by promoting AP complement activation in the sensitization and/or effector phase of asthma and therefore may represent an attractive therapeutic target for asthma. We will achieve three specific aims in this pilot project 1) to determine if genetic deficiency of properdin protects mice from allergen-induced airway inflammation and airway hyperresponsiveness (AHR) using the OVA inhalation model; 2) To create a "properdin-humanized" mouse by crossing properdin knockout mice and human properdin transgenic mice and establish a model of allergen-induced airway inflammation and AHR on this strain; 3) To determine the feasibility of therapeutic targeting of properdin in allergen-induced airway inflammation and AHR using "properdin- humanized" mice and anti-human properdin mAbs.

描述（由申请人提供）：过敏性哮喘是一个主要的公共卫生问题，在过去二十年中患病率显着增加。由于对其致病机制了解不足，目前的哮喘治疗方法（例如全身性皮质类固醇和吸入β受体激动剂）远非最佳，需要开发新的治疗方法。哮喘治疗的潜在新靶点之一是补体系统。 R21应用的重点是探讨补体蛋白备解素在哮喘发病机制中的作用及其治疗该疾病的可行性。备解素是一种血浆糖蛋白，也是唯一已知的补体级联正调节剂。它通过稳定 C3 转化酶 C3bBb 促进替代途径 (AP) 补体激活。最近的证据表明，备解素还可以作为一种模式识别分子，与选择性靶标表面结合并启动 AP 补体激活。此外，在包括 K/BxN 关节炎在内的几种 AP 补体介导的组织损伤模型中，我们发现备解素有助于疾病发病机制。本申请的总体目标是检验以下假设：备解素通过促进哮喘致敏和/或效应阶段中的AP补体激活而参与过敏性哮喘的发病机制，因此可能代表哮喘的有吸引力的治疗靶点。我们将在这个试点项目中实现三个具体目标：1) 使用 OVA 吸入模型确定备解素的遗传缺陷是否可以保护小鼠免受过敏原诱导的气道炎症和气道高反应性 (AHR) 的影响； 2）通过备解素基因敲除小鼠与人备解素转基因小鼠杂交制备“备解素人源化”小鼠，并在此品系上建立过敏原诱导的气道炎症和AHR模型； 3) 确定使用“备解素人源化”小鼠和抗人备解素单克隆抗体在过敏原诱导的气道炎症和 AHR 中治疗靶向备解素的可行性。