Lung-Liver Axis During Pneumonia

描述（由申请人提供）： 肺部感染在全球范围内造成巨大的疾病负担，是感染相关死亡的最常见原因和急性肺损伤的常见原因。候选人和他的实验室的长期目标是阐明宿主防御和预防肺损伤所需的肺内和肺外信号通路。候选人自开始研究生涯以来一直专注于肺宿主防御，并通过他的成就表现出对学术研究的坚定承诺。他正在一个成功的环境中进行研究，哈佛公共卫生学院，这是完全适合最大限度地提高他的职业发展在指导阶段，并最终，他向独立的过渡。肺部感染的预防需要由早期反应细胞因子（TNF-α和IL-1）和IL-6促进的局部炎症反应。这些细胞因子分别在很大程度上通过NF-κ B RelA和STATS进行信号传导。局部肺部免疫应答与全身急性期应答（APR）串联发生。虽然APR长期以来被认为是肺炎期间疾病进展的有用生物标志物，但介导APR的机制以及急性期蛋白（APP）对肺炎期间炎症和宿主防御的集体影响尚不清楚。拟议研究计划的中心假设是，在肺炎期间，急性期反应是由肝脏中的STATS和RelA激活诱导的，并且是肺中宿主防御所必需的。为了解决这个问题，候选人旨在测试以下特定假设：在肺炎期间，（1）肝细胞中STATS和RelA的激活和APP的表达需要TNF-α、IL-1和IL-6，（2）肝细胞中的STATS和RelA是APP表达所需的，以及（3）肝细胞中的STATS和RelA有助于肺部的炎症和宿主防御。这些研究将采用创新的方法，包括使用肝细胞靶向（Cre-LoxP介导）RelA、STATS或RelA和STATS基因缺失的小鼠。初步数据支持中心的假设和可行性的实验方法。这些研究的完成将证明调节肝脏中APP表达的机制是否可能成为肺炎或其他严重感染患者的新治疗靶点。

DESCRIPTION (provided by applicant): Lung infections account for a tremendous burden of disease worldwide, representing the most frequent cause of infection-related deaths and a common cause of acute lung injury. The long term goal of both the candidate and his laboratory is to elucidate intra- and extra-pulmonary signaling pathways required for host defense and the prevention of lung injury. The candidate has focused on pulmonary host defense since initiating his research career, and has through his accomplishments demonstrated a strong commitment to academic research. He is conducting research in a successful environment, Harvard School of Public Health, which is wholly suited to maximize his career development during the mentored phase and, ultimately, his transition toward independence. Prevention of lung infections requires a local inflammatory response that is facilitated by early response cytokines (TNF-a and IL-1) and IL-6. These cytokines signal in large part through NF-kappaB RelA and STATS, respectively. Local pulmonary immune responses occur in tandem with a systemic acute phase response (APR). Although the APR has long been recognized as a useful biomarker of disease progression during pneumonia, mechanisms mediating the APR and the collective impact of acute phase proteins (APPs) on inflammation and host defense during pneumonia are unknown. The central hypothesis of the proposed research plan is that during pneumonia, acute phase responses are induced by STATS and RelA activation in the liver and are necessary for host defense in the lung. To address this, the candidate aims to test the specific hypotheses that, during pneumonia, (1) the activation of STATS and RelA and the expression of APPs in hepatocytes require TNF-a, IL-1, and IL-6, (2) STATS and RelA in hepatocytes are required for APP expression, and (3) STATS and RelA in hepatocytes contribute to inflammation and host defense in the lungs. These studies will employ innovative approaches, including the use of mice with hepatocyte-targeted (Cre-LoxP-mediated) gene deletions of RelA, STATS or both RelA and STATS. Preliminary data support the central hypothesis and the feasibility of the proposed experimental approaches. Completion of these studies will demonstrate whether mechanisms regulating APP expression in the liver may be novel therapeutic targets for patients with pneumonia or other severe infections.