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.
This project studies the role of a protein called properdin in the pathogenesis and treatment of asthma. Properdin is normally involved in host defense against pathogenic infections, but recent studies have suggested that it may also contribute to allergic and inflammatory disorders. By using the mouse as an animal model, we will study the role of properdin in the development of asthma and explore the possibility of using anti-properdin reagents as novel therapeutic drugs for human asthma.
|Gullipalli, Damodar; Zhang, Fengkui; Sato, Sayaka et al. (2018) Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis. J Immunol 201:1021-1029|
|Wang, Yuan; Miwa, Takashi; Ducka-Kokalari, Blerina et al. (2015) Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation. J Immunol 195:1171-81|
|Lesher, Allison M; Nilsson, Bo; Song, Wen-Chao (2013) Properdin in complement activation and tissue injury. Mol Immunol 56:191-8|