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

描述(由申请人提供)： K08提案的目标是让候选人有机会：1)发展成为一名独立的研究人员，2)在分子技术、感染体内模型、细胞分选和FACS分析方面获得实验室经验，3)专注于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Jay K.Kolls博士和她的职业发展委员会的专业知识。她将受益于肺免疫实验室、兰格斯研究中心和医学院提供的资源。这项建议将研究IL-23在慢性和急性铜绿假单胞菌肺部感染中的作用。铜绿假单胞菌是囊性纤维化患者慢性支气管腔内感染的最主要原因，也是其他免疫受损群体急性肺炎相关发病率和死亡率的重要原因。宿主反应的特点是中性粒细胞浸润和严重的肺损伤。初步数据表明，IL-23是在铜绿假单胞菌感染时产生的，这会导致IL-17、CXC趋化因子和中性粒细胞反应的升高。此外，初步数据表明，IL-23受STAT-1调节，这种调节在感染时可能会改变。这导致了提出的假设：铜绿假单胞菌通过TLR4在肺内的抗原提呈细胞上发出信号，引起IL-23的产生，随后的IL-17的产生和持续的粒系反应；由I型干扰素激活的STAT1下调了这种IL-23的产生，影响了负反馈循环。1)研究肺泡巨噬细胞和肺DC亚群以TLR4依赖的方式产生IL-23的能力，2)确定实验性铜绿假单胞菌感染是否诱导肺抗原提呈细胞产生IL-23，并导致IL-17、G-CSF和CXC趋化因子的产生以及随后的中性粒细胞募集，以及3)确定STAT1是否被I型干扰素激活，下调IL-23的产生。 (摘要结束)

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)