Complement and allergic asthma

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著增加。由于对其致病机制的认识不足，目前哮喘的治疗如全身性皮质类固醇和吸入性β受体激动剂的给药远不是最佳的，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应用的重点是探索补体蛋白备解素在哮喘发病机制中的作用及其在这种疾病中治疗靶向的可行性。备解素是一种血浆糖蛋白，也是目前已知的唯一的补体级联反应正调控因子。它通过稳定C3转化酶C3 bBb促进旁路途径（AP）补体激活。最近的证据表明，备解素也可以作为模式识别分子结合到选择性靶表面并启动AP补体激活。此外，在几个AP补体介导的组织损伤模型，包括K/BxN关节炎，我们发现备解素有助于疾病的发病机制。本申请的总体目的是检验备解素通过在哮喘的致敏和/或效应阶段促进AP补体活化而参与过敏性哮喘的发病机制的假设，因此可能代表哮喘的有吸引力的治疗靶点。本研究的目的有三：1）通过卵清蛋白（OVA）吸入模型，研究备解素基因缺陷对小鼠气道炎症和气道高反应性（AHR）的保护作用; 2）通过备解素基因敲除小鼠与人备解素转基因小鼠杂交，建立备解素人源化小鼠模型; 3）使用“备解素人源化”小鼠和抗人备解素mAb确定备解素在变应原诱导的气道炎症和AHR中的治疗性靶向的可行性。

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.