Beyond the Type-2 High Endotype: Interferons and Epithelial ER Stress in Asthma

项目摘要/摘要 尽管2型细胞因子(IL-4、-5和-13)在哮喘中很重要，但有相当比例的患者 患有严重哮喘的患者对针对这一途径的新生物制剂反应不佳。因此，迫切需要 以促进我们对导致哮喘的其他非2型炎症途径的理解。这个 这项研究的长期目标是开发治疗重症哮喘的新策略，重点是非 第二类疾病机制。本申请中提供的初步数据表明，有两种非2型 可能导致哮喘的疾病机制：1)干扰素驱动的炎症和2)呼吸道 上皮性内质网(ER)应激。我们的主要假设是干扰素驱动的和2型 炎症途径独立地促进了哮喘的呼吸道功能障碍，部分是通过诱导 呼吸道上皮细胞内质网应激。为了验证这一假设，这项拨款提出了三个具体目标。具体目标1 将确定2型炎症、干扰素驱动的炎症和呼吸道之间的关系 哮喘队列中的上皮内质网应激。这个目标的第一个假设是，阻止治疗策略 哮喘中的2型炎症将使干扰素驱动的炎症和内质网应激得不到完全治疗。我们 我将使用从随机对照试验中获得的样本和数据来验证这一假设：1)吸入皮质类固醇和2) Lebrikizumab(抗IL-13)。这一目标的第二个假设是，呼吸道上皮细胞内质网应激与 干扰素驱动的炎症和2型炎症，这三种途径的存在都与 更严重的哮喘。我们将使用来自NIH重症哮喘的样本和数据来验证这一假设 研究计划。具体目标2将决定2型炎症的持久性和临床意义， 哮喘队列中干扰素驱动的炎症和呼吸道上皮细胞内质网应激。这个目标的第一个假设是 这些炎症途径和内质网应激是持久的。我们将使用 AIM 1中描述的随机对照试验和一项为期12个月的前瞻性纵向研究。这个目标的第二个假设是 干扰素驱动的炎症和内质网应激的基线水平预测靶向治疗的不良反应 2型炎症和这些途径中随时间的变化与肺功能和 哮喘控制。为了验证这一假设，我们将使用RCT和上述纵向研究。特定的 目的3是利用小鼠模型确定呼吸道上皮细胞内质网应激在哮喘中的作用。这个目标是 假设呼吸道上皮细胞内质网应激在AHR、气道炎症和黏液产生中起作用 哮喘的小鼠模型。我们将使用一种新型的特异性内质网应激小分子抑制剂来测试这一点。 在两种不同的小鼠哮喘模型中研究呼吸道上皮细胞IRE1α的条件性缺失。 这项工作的成功完成将确定干扰素驱动的炎症和ER的临床意义 哮喘中的应激，并将确定一种新开发的、特异的、小分子的内质网应激抑制物 (KIRA8)有可能成为治疗严重哮喘的新方法。

PROJECT SUMMARY/ABSTRACT Despite the importance of type-2 cytokines (IL-4, -5, and -13) in asthma, a significant percentage of patients with severe asthma respond poorly to new biologics which target this pathway. Thus, there is an urgent need to advance our understanding of alternative, non-type 2 inflammatory pathways that contribute to asthma. The long term goal of this research is to develop new therapeutic strategies for severe asthma by focusing on non- type 2 mechanisms of disease. Preliminary data presented in this application suggest two non-type 2 mechanisms of disease that may contribute to asthma: 1) interferon-driven inflammation and 2) airway epithelial endoplasmic reticulum (ER) stress. Our overarching hypothesis is that interferon-driven and type 2 inflammatory pathways independently contribute to airway dysfunction in asthma, in part through the induction of airway epithelial ER stress. To test this hypothesis, this grant proposes three specific aims. Specific aim 1 will determine the relationship between type 2 inflammation, interferon-driven inflammation and airway epithelial ER stress in asthma cohorts. This aim's first hypothesis is that therapeutic strategies which block type 2 inflammation in asthma will leave interferon-driven inflammation and ER stress incompletely treated. We will test this hypothesis using samples and data obtained from RCTs of: 1) inhaled corticosteroids and 2) Lebrikizumab (anti IL-13). This aim's second hypothesis is that airway epithelial ER stress is associated with both interferon-driven and type 2 inflammation and that the presence of all three pathways is associated with more severe asthma. We will test this hypothesis using samples and data from the NIH Severe Asthma Research Program. Specific aim 2 will determine the durability and clinical significance of type 2 inflammation, interferon-driven inflammation and airway epithelial ER stress in asthma cohorts. This aim's first hypothesis is that these inflammatory pathways and ER stress are durable over time. We will test this hypothesis using the RCTs described in aim 1 and a prospective 12-month longitudinal study. This aim's second hypothesis is that baseline levels of interferon-driven inflammation and ER stress predict poor response to therapies targeting type 2 inflammation and that change over time in these pathways correlates change in lung function and asthma control. To test this hypothesis, we will use the RCTs and longitudinal study described above. Specific aim 3 is to determine the role of airway epithelial ER stress in asthma using murine models. This aim's hypothesis is that airway epithelial ER stress contributes to AHR, airway inflammation and mucus production in mouse models of asthma. We will test this using a novel specific small molecule inhibitor of ER stress and studying a conditional deletion of IRE1α in airway epithelial cells in two different murine asthma models. Successful completion of this work will identify the clinical significance of interferon-driven inflammation and ER stress in asthma, and will determine whether a newly-developed, specific, small molecule inhibitor of ER stress (KIRA8) has potential as a new therapeutic approach for severe asthma.