The Role of Oncostatin-M in Pneumonia

制瘤素-M 在肺炎中的作用

• 批准号: 9335424
• 负责人: Katrina Traber
• 金额: $ 16.42万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335424
• 关键词: Accounting; Acute; Acute Lung Injury; Alveolar; Alveolar Macrophages; Automobile Driving; Bacteria; Bacterial Pneumonia; Binding; Biology; Boston; CXCL5 gene; Cells; Characteristics; Clinical; Communities; Critical Care; Cytokine Signaling; Data; Disease; Doctor of Philosophy; Effector Cell; Epithelial; Epithelial Cells; Epithelium; Event; Faculty; Family; Fellowship; Fostering; Future; Genes; Goals; Human; Immune response; Immune signaling; Immunity; Immunologics; Immunology; Immunomodulators; Infection; Inflammation; Innate Immune Response; Innate Immune System; Interleukin-6; Intervention; Investigation; Knowledge; Laboratories; Lung; Lung diseases; Measurable; Mediating; Medicine; Mentors; Methods; Microbiology; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Neutrophil Infiltration; Outcome; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Physicians; Pluripotent Stem Cells; Pneumonia; Prevention; Public Health; Pulmonary Inflammation; Recruitment Activity; Research; Research Methodology; Research Training; Respiratory Tract Infections; Role; STAT3 gene; Scientist; Shapes; Signal Pathway; Signal Transduction; Source; Techniques; Testing; Therapeutic; Training; Training Programs; Tweens; Universities; Vocational Guidance; Work; antimicrobial; base; burden of illness; career; chemokine; cytokine; design; improved; in vitro Model; in vivo; medical schools; member; mortality; neutralizing antibody; neutrophil; novel; novel diagnostics; oncostatin M; pathogenic bacteria; prognostic; programs; promoter; receptor; response; transcription factor; transcriptome

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.

项目概要/摘要 急性细菌性肺炎是全世界发病率和死亡率的重要来源，但我们的理解 参与肺部免疫反应的早期信号通路仍然有限。 肺炎时，先天免疫系统会快速检测到致病菌，从而产生级联效应 激活常驻细胞并招募效应细胞（如中性粒细胞）以促进抗菌的分子 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因素。 肺炎的早期信号，我们也许能够根据细胞因子模式或 我们的初步结果首次表明，改变其治疗功能的免疫调节剂。 IL-6 家族细胞因子制瘤素 M (OSM) 增强肺炎期间的先天免疫。 这种反应仍然未知，我们发现 OSM 塑造肺转录组来指导 我们将首先集中精力剖析肺泡中性粒细胞募集的来源、目标和结果。 OSM 在肺炎期间的后果，特别强调我们发现的一种新的 STAT3-CXCL5 轴 为此，我们将追求以下三个目标。 检验我们的中心假设，即骨髓源性制瘤素 M 靶向肺上皮以激活基因 肺炎期间导致急性肺部炎症的程序。 目标 1 – 检验 OSM 由肺泡巨噬细胞产生并招募中性粒细胞来产生的假设 促进肺炎期间的急性炎症。 目标 2 – 检验 OSM 通过其受体 OSMRβ 直接调节肺上皮细胞的假设 促进肺炎期间的先天免疫。 目标 3 – 检验 Cxcl5 诱导和最大中性粒细胞募集需要 STAT3 介导的假设 肺炎期间的 OSM 信号传导。 Traber 博士将进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 通过正式的计划，促进她向独立医师科学家的职业生涯过渡。 通过教学和一对一的培训，她将发展肺部先天免疫方面的专业知识并掌握 在这个项目中，她将与她的导师 Lee 博士密切合作。 昆顿和约瑟夫·米兹格德都是肺部先天免疫领域的专家，她也将接受治疗。 来自其他几位具有广泛专业知识的教员的科学和职业指导 凭借她在微生物学（博士培训）、肺和疾病方面的综合专业知识。 重症监护医学（临床培训）和肺免疫学（研究员研究培训） Traber 博士状况良好 具有开展该项目的资格。拟议的研究将在波士顿肺科中心进行。 大学医学院是一个以尖端肺部疾病研究而闻名的部门， 合作精神以及医师科学家的精湛培训。