Macrophages in steroid resistant asthma

类固醇抵抗性哮喘中的巨噬细胞

基本信息

批准号：
10705009
负责人：
BRANDON LEWIS
金额：
$ 2.33万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2023-07-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705009
关键词：
Adoptive Transfer Adrenal Cortex Hormones Air Movements Antiinflammatory Effect Apoptotic Asthma Bone Marrow Cells Child Childhood Childhood Asthma Chronic Development Disease Dose Enzyme-Linked Immunosorbent Assay Exhibits Exposure to Foundations Future Glucocorticoid Receptor Goals Grant Hemophilus Histologic Homeostasis Host Defense Human Immune Immune response Immunologics Infiltration Inflammation Inflammation Mediators Inflammatory Inhalation Interferon Type II Interleukin-13 Interleukin-4 Interleukin-6 Learning Skill Liposomes Lung Lung diseases Lymphocyte Macrophage Macrophage Activation Measures Mediating Modeling Molecular Mucous body substance Mus Natural Immunity Newborn Infant Ovalbumin Pathogenesis Pathway interactions Patients Phenotype Postdoctoral Fellow Production Quality of life Receptor Signaling Research Resistance Role Second Messenger Systems Severities Steroid Resistance Steroid-resistant asthma Steroids Stimulator of Interferon Genes Streptococcus Structure Symptoms TNF gene Techniques Testing Western Blotting adaptive immune response adverse outcome airway hyperresponsiveness airway inflammation airway obstruction allergic airway inflammation aluminum sulfate asthmatic cytokine experience improved in vitro Model inflammatory milieu mouse model novel particle pathogen post-doctoral training pulmonary function response sensor side effect transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY Pediatric asthma is a chronic pulmonary inflammatory disease that is causes airway inflammation and restricted airflow. Patients with severe asthma are resistant to steroid treatment, which leads to worsened symptoms and exacerbations. While asthma is known to involve T-helper 2 (Th2) inflammation, recent studies suggest steroid resistant asthmatics have a predominant Th1 inflammatory profile, involving IFNγ and Th1 lymphocytes. Although the adaptive immune response has been shown to mediate steroid resistance in asthma, the contributions of the innate immune cells, such as macrophages are not well understood. Lung macrophages, either classically- or alternatively-activated, are known to produce and secrete cytokines that are involved in Th2 and Th1 inflammation, making them highly relevant to asthma pathogenesis. Previous studies have shown that macrophages have an important role in asthma, yet little is known about macrophage contributions to steroid resistance and severe asthma. Using an augmented ovalbumin mouse model and primary mouse and human macrophages, we will investigate macrophages and their contributions to airway inflammation, airway and hyperresponsiveness in 2 Specific Aims. Studies in Aim 1 will determine the role of steroid resistant lung macrophages in a mouse model of allergic airway inflammation using lung macrophage depletion and adoptive transfer techniques. In Aim 2, this proposal will examine the mechanisms by which IRF5, a pro-inflammatory transcription factor, disrupts glucocorticoid receptor signaling in classically-activated macrophages. These studies will be conducted using cultured primary mouse bone marrow derived macrophages. To further assess steroid resistant pathways in lung macrophages, RNA-seq analysis will be performed. Additionally, steroid sensitivity will also be assessed in classically-activated human lung macrophages. Importantly, these studies are supplemented with a comprehensive postdoctoral training plan that will enhance the scientific and professional development of a promising postdoctoral fellow. The concepts and skills learned will provide a foundation for future pathway to independence grants such as the K99/R00.

项目概要小儿哮喘是一种慢性肺部炎症性疾病，会导致气道炎症和严重哮喘患者对类固醇治疗有抵抗力，从而导致病情恶化。虽然已知哮喘与辅助性 T 细胞 2 (Th2) 炎症有关，但最近的研究表明。表明类固醇抵抗性哮喘患者具有主要的 Th1 炎症特征，涉及 IFNγ 和 Th1 尽管适应性免疫反应已被证明可以介导哮喘的类固醇抵抗，先天免疫细胞（例如肺巨噬细胞）的贡献尚不清楚。已知无论是经典激活还是替代激活，都会产生和分泌参与 Th2 的细胞因子和 Th1 炎症，使它们与哮喘发病机制高度相关。巨噬细胞在哮喘中发挥重要作用，但人们对巨噬细胞对类固醇的贡献知之甚少使用增强卵白蛋白小鼠模型以及原代小鼠和人类。巨噬细胞，我们将研究巨噬细胞及其对气道炎症、气道和 2 个具体目标中的高反应性。目标 1 中的研究将确定类固醇抵抗性肺的作用。使用肺巨噬细胞耗竭和过继的小鼠过敏性气道炎症模型中的巨噬细胞在目标 2 中，该提案将研究促炎剂 IRF5 的机制。转录因子，破坏经典激活的巨噬细胞中的糖皮质激素受体信号传导。将使用培养的原代小鼠骨髓来源的巨噬细胞进行研究以进一步评估。肺巨噬细胞中的类固醇抗性途径，还将进行 RNA-seq 分析。重要的是，这些研究也将在经典激活的人肺巨噬细胞中进行敏感性评估。并辅以完善的博士后培养计划，提升博士后的科学性和专业性所学到的概念和技能将为有前途的博士后研究员的发展奠定基础。未来获得独立补助金的途径，例如 K99/R00。