Lung-Liver Axis During Pneumonia

描述(由申请人提供)： 肺部感染在全世界造成了巨大的疾病负担，是与感染有关的死亡的最常见原因，也是急性肺损伤的常见原因。候选人和他的实验室的长期目标都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。自从开始他的研究生涯以来，这位候选人一直专注于肺部宿主防御，并通过他的成就展示了对学术研究的坚定承诺。他在一个成功的环境中进行研究，哈佛公共卫生学院完全适合在指导阶段最大限度地促进他的职业发展，并最终过渡到独立。预防肺部感染需要局部炎症反应，这种反应由早期反应细胞因子(TNF-a和IL-1)和IL-6促进。这些细胞因子在很大程度上分别通过NF-kappaB relA和STATS来传递信号。局部肺免疫反应与全身性急性时相反应(APR)同时发生。虽然APR长期以来一直被认为是肺炎期间疾病进展的有用生物标志物，但介导APR的机制以及急性时相蛋白(APP)在肺炎期间对炎症和宿主防御的集体影响尚不清楚。提出的研究计划的中心假设是，在肺炎期间，肝脏中的STATS和RELA激活诱导了急性期反应，是肺部宿主防御所必需的。为了解决这一问题，候选人旨在测试以下特定假设：(1)在肺炎期间，(1)肝细胞中STATS和RELA的激活以及APP的表达需要肿瘤坏死因子-a、IL-1和IL-6，(2)肝细胞中的STATS和RERA是APP表达所必需的，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或同时缺失relA和STATS基因的小鼠。初步数据支持中心假设和所提出的实验方法的可行性。这些研究的完成将证明调节肝脏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.