A correctable immune-epithelial pathway for lung disease

About This Grant

Summary Chronic lung disease is still a major cause of morbidity and mortality, largely due to asthma and COPD. In both cases, poor outcome is linked to a muco-obstructive disease phenotype manifest by airway inflammation and mucus production that is commonly triggered by inhaled allergen, smoke, or pollution, and respiratory viral infection. Our goal is to define the pathway from these generally acute stimuli to chronic muco-obstructive disease and deliver a corresponding therapy. We reasoned that chronicity might best be explained by a renewable epithelial stem cell population that is reprogrammed from homeostatic to excess activation. In that context, we identified a distinct subset of basal-epithelial cell stem cells (basal-ESCs) that drive muco-obstructive disease phenotype in models of long-lasting post-viral lung disease (PVLD). Here we propose to define the define and correct basal-ESC reprograming following on our discovery of two key elements: (1) a virus-activated, monocyte-derived dendritic cell (moDC) niche that provides stem cell-like factor glycoprotein non-metastatic melanoma protein B (GPNMB) to activate CD44-receptor on basal-ESCs for overgrowth and immune activation; and (2) a coordinated mitogen-activated protein kinase 13 (MAPK13) in basal-ESCs that propagates the CD44 signal for overgrowth and immune activation and separately orchestrates mucinous differentiation in basal-ESCs and mucus production in basal-epithelial lineage secretory cells. We propose that this combination is responsible for persistent basal-ESC reprogramming that is manifest as airway inflammation (generally type-2) and excess mucus production. Indeed, we find a shared MAPK13 mechanism also drives muco-obstructive phenotype in a mouse model of allergen challenge, underlining the broader clinical relevance to airway inflammation and mucus production. To address corresponding treatment, we also propose continued studies of a first-in-kind MAPK13 inhibitor (NuP-4) (37-40, 42). We aim to use this compound as a tool to define basal-ESC control that is specific for overgrowth and immune activation versus mucus production. This approach derives from data that MAPK13 control of overgrowth and immune activation depend on conventional MAPK13 catalytic activity at the nM level whereas mucus production depends on noncatalytic MAPK13 binding activity at the pM level. We propose to segregate these activities in human cell and molecular models that can be validated in viral-infection and allergen-challenge mouse models with precisely tailored drug structure, delivery, and dose. To define a distinct and correctable immune-epithelial pathway, we propose two Specific Aims. Aim 1 will study mouse models of the disease process using genetic strategies for conventional and basal-cell specific MAPK13 knockdown and pharmacologic strategies for MAPK13 blockade at nM and pM levels. Aim 2 will study human cell and molecular models using genetic strategies for MAPK13 knockdown and overexpression and pharmacologic strategies for MAPK13 blockade at nM and pM levels. For each Aim, these strategies will include conditions that result selectively in excess mucus production and blockade to establish a specific control mechanism.