Macrophages in steroid resistant asthma

项目摘要 儿童哮喘是一种慢性肺部炎症性疾病， 气流受限。严重哮喘患者对类固醇治疗有抵抗力，导致病情恶化。 症状和恶化。虽然已知哮喘涉及辅助性T细胞2（Th2）炎症，但最近的研究表明， 提示激素抵抗性哮喘患者具有主要Th1炎症特征，包括IFN γ和Th1 淋巴细胞虽然适应性免疫反应已被证明介导哮喘中的类固醇抵抗， 先天性免疫细胞如巨噬细胞的作用还不清楚。肺巨噬细胞， 无论是经典激活还是交替激活，已知都能产生和分泌参与Th2 和Th1炎症，使它们与哮喘发病机制高度相关。以前的研究已经表明 巨噬细胞在哮喘中起重要作用，但巨噬细胞对类固醇激素的作用知之甚少。 抵抗和严重哮喘。使用增强的卵清蛋白小鼠模型和原代小鼠和人 巨噬细胞，我们将研究巨噬细胞及其对气道炎症，气道和 高反应性2个具体目标。目标1的研究将确定类固醇耐药肺的作用 使用肺巨噬细胞耗竭和过继性巨噬细胞在小鼠过敏性气道炎症模型中的表达 转移技术。在目标2中，该提议将研究IRF5，一种促炎因子， 转录因子，破坏经典活化的巨噬细胞中的糖皮质激素受体信号传导。这些 将使用培养的原代小鼠骨髓衍生的巨噬细胞进行研究。为了进一步评估 对于肺巨噬细胞中的类固醇抗性途径，将进行RNA-seq分析。此外，类固醇 还将在经典活化的人肺巨噬细胞中评估敏感性。重要的是，这些研究 辅以全面的博士后培养计划，将提高科学性和专业性 培养一个有前途的博士后。所学的概念和技能将为以下方面奠定基础： 未来获得独立赠款的途径，如K99/R00。

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.