Neuro-immune-stromal pathways sense environmental change to regulate repair versus remodelling during airway disease (360G-Wellcome-220254_Z_20_Z)

This application will test the hypothesis that pulmonary immune homeostasis is maintained by a network of tissue resident cells that continually monitor environmental change. Disruption of local neuro-immune-stromal interactions either by genetic or environmental factors, alters the threshold for immune responses to usually innocuous particles such as dust, pollen or dander leading to chronic airway inflammation and tissue remodelling. I will ascertain the cellular and molecular composition of the airway wall parenchyma in children and adults with severe asthma and use machine learning tools and mouse models to determine the impact on lung function. Viral infection and pollution are common triggers for asthma severity, and I will establish how the immune/stromal niche communicates with the external environment to react to these inhaled stimuli, focussing on interaction with neuronal systems. I will examine how these interactions differ in severe asthma and contribute to the ensuing inflammation, remodelling and lung dysfunction. I will investigate the cellular interactions between fibroblasts, extracellular matrix and type 2 immune cells that facilitate repair versus remodelling during severe asthma. Ultimately this programme will reveal insight into mechanisms underlying tissue remodelling versus repair during severe asthma.