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，在过去的二十年中发病率显著增加。由于对其致病机制的认识不足，目前的哮喘治疗方法，如全身性皮质类固醇和吸入β受体激动剂的使用远远不够理想，需要开发新的治疗方法。补体系统是哮喘治疗的潜在新靶点之一。本次R21申请的重点是探讨补体蛋白properdin在哮喘发病机制中的作用及其治疗靶向的可行性。Properdin是一种血浆糖蛋白，是唯一已知的补体级联的正调节因子。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，properdin也可能作为一种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properdin参与了疾病的发病机制。本应用的总体目标是验证普萘丁在哮喘致敏期和/或效应期通过促进AP补体激活参与过敏性哮喘发病机制的假设，因此可能代表一个有吸引力的哮喘治疗靶点。在这个试点项目中，我们将实现三个具体目标：1)使用OVA吸入模型确定properdin基因缺陷是否能保护小鼠免受过敏原诱导的气道炎症和气道高反应性（AHR）；2)将properdin敲除小鼠与人properdin转基因小鼠杂交，建立“properdin人源化”小鼠，并在该品系上建立过敏原诱导的气道炎症和AHR模型；3)利用“properdin人源化”小鼠和抗人properdin单抗，确定properdin靶向治疗过敏原诱导的气道炎症和AHR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.