Macrophages in steroid resistant asthma

项目总结 儿童哮喘是一种慢性肺部炎症性疾病，可引起呼吸道炎症和 气流受限。严重哮喘患者对类固醇治疗有抵抗力，这会导致病情恶化。 症状和恶化。虽然已知哮喘与T辅助细胞2(Th2)炎症有关，但最近的研究 提示激素抵抗型哮喘患者具有主要的Th1型炎症特征，包括干扰素γ和Th1 淋巴细胞。虽然获得性免疫反应已被证明在哮喘中介导类固醇抵抗， 巨噬细胞等先天免疫细胞的作用还不是很清楚。肺巨噬细胞， 无论是经典激活的还是交替激活的，都能产生和分泌与Th2有关的细胞因子 和Th1炎症，使它们与哮喘的发病机制高度相关。此前的研究表明， 巨噬细胞在哮喘中起重要作用，但对巨噬细胞对类固醇激素的作用知之甚少。 抵抗力和严重哮喘。使用增强的卵白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在呼吸道炎症、呼吸道和 2个特定目标的高反应性。AIM 1的研究将确定类固醇耐药肺的作用 肺巨噬细胞耗尽和过继致小鼠过敏性呼吸道炎症模型中的巨噬细胞 转移技术。在目标2中，这项提案将审查IRF5，一种促炎剂 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。这些 研究将使用培养的原代小鼠骨髓来源的巨噬细胞进行。进一步评估 对于肺巨噬细胞中的类固醇耐药途径，将进行RNA-seq分析。此外，类固醇 敏感性也将在经典激活的人肺巨噬细胞中进行评估。重要的是，这些研究是 辅以全面的博士后培训计划，将提高科学和专业 培养一位有前途的博士后研究员。学到的概念和技能将为 未来获得独立资助的途径，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.