Lung-Liver Axis During Pneumonia

肺炎期间的肺肝轴

基本信息

批准号：
8288115
负责人：
Lee Quinton
金额：
$ 24.65万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288115
关键词：
Accounting Acute Lung Injury Acute-Phase Proteins Acute-Phase Reaction Address Alveolar Amyloid Apoptotic Bacterial Pneumonia Binding Biological Biological Markers Biological Process Blood C-reactive protein Cell Line Cells Cessation of life Chemotaxis Complement Cytokine Signaling Data Disease Progression Edema Environment Escherichia Escherichia coli Gene Deletion Gene Expression Genes Goals Hepatic Hepatocyte Host Defense Immune response In Vitro Individual Infection Infection prevention Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-6 Laboratories Liver Lower respiratory tract structure Lung Measures Mediating Mediator of activation protein Mentors Messenger RNA Mus NF-kappa B Natural Immunity Neutrophil Infiltration Outcome Patients Phagocytosis Phase Plasma Plasma Proteins Pneumonia Prevention Protein Binding Proteins Public Health Schools Recombinant Cytokines Research Role STAT3 gene Serum Serum amyloid A protein Signal Pathway Signal Transduction Small Interfering RNA Stat3 protein Streptococcus pneumoniae System Testing Transcriptional Regulation Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha base burden of illness career career development chromatin immunoprecipitation cytokine in vivo innovation knock-down leukocyte activation lipopolysaccharide-binding protein loss of function lung injury microbial neutralizing antibody new therapeutic target novel strategies programs promoter protein expression response tool transcription factor

项目摘要

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.

描述（由申请人提供）：肺部感染在全世界造成巨大的疾病负担，是感染相关死亡的最常见原因，也是急性肺损伤的常见原因。候选人及其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传导途径。该候选人自开始研究生涯以来一直专注于肺部宿主防御，并通过他的成就表明了对学术研究的坚定承诺。他正在哈佛大学公共卫生学院这样一个成功的环境中进行研究，这完全适合他在指导阶段实现职业发展最大化，并最终实现他向独立的过渡。预防肺部感染需要早期反应细胞因子（TNF-a 和 IL-1）和 IL-6 促进局部炎症反应。这些细胞因子在很大程度上分别通过 NF-kappaB RelA 和 STATS 发出信号。局部肺部免疫反应与全身急性期反应（APR）同时发生。尽管 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 的机制以及肺炎期间急性期蛋白 (APP) 对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 激活引起的，并且是肺部宿主防御所必需的。为了解决这个问题，候选人旨在测试以下具体假设：在肺炎期间，(1) STATS 和 RelA 的激活以及肝细胞中 APP 的表达需要 TNF-a、IL-1 和 IL-6，(2)肝细胞中的 STATS 和 RelA 是 APP 表达所必需的，并且 (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方法，包括使用肝细胞靶向（Cre-LoxP 介导）RelA、STATS 或 RelA 和 STATS 基因删除的小鼠。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肝脏中 APP 表达的调节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。