The Role of Oncostatin-M in Pneumonia

项目总结/摘要 急性细菌性肺炎是全球发病率和死亡率的重要来源，但我们的理解是， 参与肺部免疫反应的早期信号通路仍然有限。期间 在肺炎中，先天免疫系统迅速检测病原菌，导致效应子级联反应。 激活驻留细胞并募集效应细胞（如中性粒细胞）以促进抗微生物 防御细胞因子可能是这些因素中最突出的。我们希望通过了解这些 肺炎的早期信号，我们可能能够开发基于细胞因子模式的新诊断方法， 治疗性免疫调节剂，改变其功能。我们的初步结果首次表明， IL-6家族细胞因子Oncostatin-M（OSM）在肺炎期间强化先天免疫。虽然， 这种反应仍然未知，我们发现OSM塑造了肺转录组， 肺泡中性粒细胞募集我们将集中我们的初步努力解剖的来源，目标， 肺炎期间OSM的后果，特别强调了一种新的STAT 3-CXCL 5轴， 作为OSM驱动的免疫应答的中间体。为此，我们将努力实现以下三个目标 为了验证我们的中心假设，即骨髓来源的抑瘤素M靶向肺上皮细胞， 在肺炎期间驱动急性肺部炎症的程序。 目的1 -检验OSM是由肺泡巨噬细胞和募集的中性粒细胞产生的假设， 促进肺炎期间的急性炎症。 目的2 -检验OSM通过其受体OSMRβ直接调节肺上皮细胞的假设， 在肺炎期间促进先天免疫。 目的3 -检验Cxc 15诱导和最大中性粒细胞募集需要STAT 3介导的免疫调节的假设。 肺炎期间的OSM信号。 博士Traber将执行本提案中概述的研究，作为设计的更大培训计划的一部分 促进她向独立的医学科学家的职业生涯过渡。通过一个正式的 教学法和一对一的培训，她将发展在肺部先天免疫和硕士专业知识 先进的研究方法。在这个项目中，她将与她的导师李博士密切合作， Quinton和Joseph Mizgerd都是肺部先天免疫领域的专家。她还将收到 科学和职业指导，从几个额外的教师与广泛的专业知识， 肺病研究。凭借她在微生物学（博士学位）方面的综合专业知识，训练），肺和 重症监护医学（临床培训）和肺免疫学（奖学金研究培训）Traber博士很好 有资格承担这个项目。拟定研究将在波士顿肺中心进行 大学医学院是一个以尖端肺部疾病研究而闻名的系， 医生科学家的合作和高超的训练。

PROJECT SUMMARY/ABSTRACT Acute bacterial pneumonia is a significant source of morbidity and mortality worldwide, but our understanding of the early signaling pathways involved in the pulmonary immune response remains limited. During pneumonia, the innate immune system rapidly detects pathogenic bacteria, leading to a cascade of effector molecules that activate resident cells and recruit effector cells such as neutrophils to promote antimicrobial defense. Cytokines are perhaps the most prominent of these factors. It is our hope that by understanding these early signals in pneumonia, we may be able to develop novel diagnostics based on cytokine patterns or therapeutic immunomodulators that alter their function. Our preliminary results are the first to indicate that the IL-6 family cytokine Oncostatin-M (OSM) fortifies innate immunity during pneumonia. While the mechanisms of this response remain unknown, we have found that OSM shapes the pulmonary transcriptome to guide alveolar neutrophil recruitment. We will focus our initial efforts on dissecting the sources, targets, and consequences of OSM during pneumonia, with particular emphasis on a novel STAT3-CXCL5 axis that we posit as an intermediate of OSM-driven immune responses. To do this, we will pursue the following three aims to test our central hypothesis that myeloid-derived Oncostatin M targets lung epithelium to activate gene programs driving acute pulmonary inflammation during pneumonia. Aim 1 – Test the hypothesis that OSM is produced by alveolar macrophages and recruited neutrophils to promote acute inflammation during pneumonia. Aim 2 – Test the hypothesis that OSM directly modulates lung epithelial cells through its receptor, OSMRβ, to promote innate immunity during pneumonia. Aim 3 – Test the hypothesis that Cxcl5 induction and maximal neutrophil recruitment require STAT3-mediated OSM signaling during pneumonia. Dr. Traber will be performing the studies outlined in this proposal as part of a larger training program designed to foster her transition towards a career as an independent physician-scientist. Through a program of formal didactics and one-one on training, she will develop expertise in pulmonary innate immunity and master advanced research methodologies. During this project, she will work closely with her mentors, Drs. Lee Quinton and Joseph Mizgerd, both experts in the field of pulmonary innate immunity. She will also receive scientific and career guidance from several additional faculty members with wide-ranging expertise in pulmonary disease research. With her combined expertise in microbiology (Ph.D. training), pulmonary and critical care medicine (clinical training), and lung immunology (fellowship research training) Dr. Traber is well qualified to undertake this project. The proposed studies will be performed at the Pulmonary Center of Boston University School of Medicine, a department with a reputation for cutting edge pulmonary disease research, collegiality, and superb training of physician scientists.