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 IRE1? 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.
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