Regulation and function of STAT3 during pneumonia

描述（由申请方提供）：肺炎是美国感染性死亡的主要原因，也是急性肺损伤的最常见潜在因素。社区获得性肺炎最常由肺炎链球菌引起，而医院获得性肺炎通常由革兰氏阴性肠道细菌如大肠杆菌引起。在对抗细菌的同时防止肺损伤需要精确调控由细胞因子-转录因子网络介导的基因表达。我们的长期目标是阐明这些信号网络，以便可以操纵细胞因子和转录因子来改善宿主防御和预防肺损伤。细胞因子IL-6在细菌性肺炎期间对中性粒细胞募集和细菌清除是必需的。转录因子STAT 3可被IL-6激活，在预防高氧肺损伤中起重要作用。我们的主要目的是确定肺炎期间肺中STAT 3是否被激活，解读肺炎期间调节STAT 3激活的上游通路，并确定增加STAT 3活性是否在肺炎期间保护肺。基于我们的初步研究结果，我们提出了一个核心假设，即STAT 3在E. coli和革兰氏阳性菌S.以增加中性粒细胞募集并防止肺损伤。为了检验这一中心假设，我们开发了一些策略，用于使用质粒转染在体内研究肺中的基因诱导和转录因子功能，以及使用蛋白质组学在体内鉴定肺中活化的转录因子。通过这些方法，我们将追求以下具体目标：（1）验证在E.（2）验证S.肺炎性肺炎，STAT 3被多种IL-6家族细胞因子激活，其表达需要TNF α和IL-1受体的NF-κ B激活，（3）以检验肺炎期间肺中STAT 3活性增加中性粒细胞募集并减少肺损伤的假设，和（4）鉴定肺炎期间依赖于IL-6的除STAT 3之外的转录调节因子。阐明IL-6和STAT 3在肺炎过程中的调控和功能，将为改善宿主防御和预防肺部感染或有肺部感染风险患者的肺损伤提供分子靶点。

DESCRIPTION (provided by applicant): Pneumonia is the leading cause of infectious deaths in the U.S. and the most common factor underlying acute lung injury. Community acquired pneumonias are most often caused by Streptococcus pneumoniae, whereas nosocomial pneumonias are commonly caused by Gram-negative enteric bacteria such as Escherichia coli. Fighting bacteria while preventing lung injury requires precisely regulated gene expression mediated by cytokine-transcription factor networks. Our long-term goals are to elucidate these signaling networks so that cytokines and transcription factors may be manipulated to improve host defense and prevent lung injury. The cytokine IL-6 is essential to neutrophil recruitment and bacterial clearance during bacterial pneumonia. The transcription factor STAT3 can be activated by IL-6, and is critical to preventing lung injury after hyperoxia. Our broad objectives are to determine whether STAT3 is activated in the lungs during pneumonia, to decipher the upstream pathways regulating STAT3 activation during pneumonia, and to determine whether increasing STAT3 activity protects the lungs during pneumonia. Based on results from our preliminary studies, we have formulated the central hypothesis that STAT3 is activated by different upstream cytokine pathways during E. coli and S. pneumoniae pneumonias to increase neutrophil recruitment and prevent lung injury. To test this central hypothesis, we have developed strategies for studying gene induction and transcription factor function in the lungs in vivo, using plasmid transfection, and for identifying transcription factors activated in the lungs in vivo, using proteomics. With these approaches, we will pursue the following specific aims: (1) to test the hypothesis that STAT3 activation requires IL-6 during E. coli pneumonia, (2) to test the hypothesis that, during S. pneumoniae pneumonia, STAT3 is activated by multiple IL-6 family cytokines whose expression requires NF-KappaB activation from receptors for TNFalpha and IL-1, (3) to test the hypothesis that STAT3 activity in the lungs increases neutrophil recruitment and decreases lung injury during pneumonia, and (4) to identify transcriptional regulators other than STAT3 that depend on IL-6 during pneumonia. Elucidating the regulation and function of IL-6 and STAT3 during pneumonia will provide molecular targets for improving host defense and preventing lung injury in patients with or at risk for lung infections.