IL-23: Actions and Regulation in Pseudomonas aeruginosa Pulmonary Infection

描述（由申请人提供）： 本K 08提案的目标是让候选人有机会：1）发展成为独立的研究者，2）获得分子技术、体内感染模型和细胞分选以及FACS分析方面的实验室经验，3）关注IL-23在铜绿假单胞菌肺炎中的作用。候选人将利用她的导师杰伊·K博士的专业知识。科尔斯和她的职业发展委员会。她将受益于肺免疫学实验室，范围研究中心和医学院的可用资源。本研究将探讨IL-23在慢性和急性铜绿假单胞菌肺部感染中的作用。肺炎支原体是囊性纤维化患者慢性支气管内感染的最重要原因，也是其他免疫功能低下人群中与急性肺炎相关的发病率和死亡率的重要原因。宿主反应的特征是嗜中性粒细胞浸润和显著的肺损伤。初步数据表明，IL-23响应于铜绿假单胞菌感染而产生，并且这导致升高的IL-17、CXC趋化因子和嗜酸性应答。此外，初步数据表明IL-23受STAT-1调节，并且这种调节可能在感染时发生改变。这导致了所提出的假设：铜绿假单胞菌通过肺中抗原呈递细胞上的TLR 4进行信号传导，刺激IL-23产生，随后产生IL-17和持续的粒细胞生成应答; I型IFN激活STAT 1下调IL-23产生，产生负反馈回路。将通过以下具体目标对这一假设进行研究：1）研究肺泡巨噬细胞和肺DC亚群以TLR 4依赖性方式响应铜绿假单胞菌产生IL-23的能力，2）确定实验性铜绿假单胞菌感染是否刺激肺抗原呈递细胞产生IL-23并导致IL-17，G-CSF和CXC趋化因子产生以及随后的中性粒细胞募集和3）确定STAT 1是否被I型IFN激活，下调IL-23产生。 (End摘要）

DESCRIPTION (provided by applicant): The goal of this K08 proposal is to allow the candidate the opportunity to: 1) develop into an independent investigator, 2) gain laboratory experience in molecular techniques, in vivo models of infection and cell sorting and FACS analysis and 3) focus on the role of IL-23 in Pseudomonas aeruginosa pneumonia. The candidate will draw on the expertise of her mentor Dr. Jay K. Kolls and her Career Development Committee. She will benefit from the resources available in the Lung Immunology Laboratory, Ranges Research Center and the School of Medicine. This proposal will examine the role of IL-23 in both chronic and acute P. aeruginosa pulmonary infection. P. Aeruginosa is the most significant cause of chronic endobronchial infection in individuals with cystic fibrosis and is also a significant cause of morbidity and mortality related to acute pneumonia in other, immunocompromised groups. The host response is characterized by neutrophilic infiltration and significant pulmonary damage. Preliminary data suggest that IL-23 is produced in response to P. aeruginosa infection and that this results in elevated IL-17, CXC chemokines and a neutrophilic response. In addition, preliminary data suggest that IL-23 is regulated by STAT-1 and that this regulation may be altered in the face of infection. This has led to the proposed hypothesis that: P. aeruginosa, signaling through TLR4 on antigen presenting cells in the lung, elicits IL-23 production, subsequent IL-17 production and an ongoing granulopoietic response; STAT1 activation by Type I IFN down-regulates this IL-23 production, effecting a negative feedback loop. This hypothesis will be investigated by the following specific aims: 1) To investigate the capacity of alveolar macrophages and lung DC subsets to produce IL-23 in response to P. aeruginosa in a TLR4 dependent fashion, 2) To determine if experimental P. aeruginosa infection elicits IL-23 production by lung antigen presenting cells and results in IL-17, G-CSF and CXC chemokine production as well as subsequent neutrophil recruitment and 3) To determine if STAT1 is activated by Type I IFN, down-regulating IL-23 production. (End of Abstract)