Wednesday, April 2, 2025
4/2/2025
Interoceptors controlling airway constriction - Project Summary Asthma, characterized by airway inflammation, airflow obstruction, and airway hyperresponsiveness, is an increasingly common inflammatory airway disease that affects 10% of the world's population. Given that anti- inflammatory treatment only partially controls asthma symptoms, it is urgent to understand the involvement of non-immune systems in the disease. Emerging evidence suggest that lung interoceptors, sensory nerves monitoring the internal states, play a key role in the development of asthma symptoms. Our recent studies discovered that MrgprC11+ jugular sensory neurons control cholinergic bronchoconstriction and airway hyperresponsiveness. Ablation of MrgprC11+ neurons reduced airway hyperresponsiveness without affecting the allergic inflammation in a mouse asthma model. Furthermore, our preliminary data suggest that asthmatic cytokines modulate the neuronal activity of MrgprC11+ neurons and sensitize cholinergic bronchoconstriction. In this proposal, we will use Cre-dependent labeling, transcriptomic, epigenomic, and mouse airway mechanic analysis combined with a novel calcium imaging technique to investigate how MrgprC11+ neurons contribute to airway hyperresponsivness in asthma. Aim 1 will focus on the transcriptomic and epigenomic analysis of MrgprC11+ neurons in asthma to understand how lung interoceptors respond to allergic airway inflammation. Aim 2 will investigate how the airway inflammation modulates the electrophysiological properties of MrgprC11+ neurons and changes the neuronal responses of airway-innervating nerves. In Aim 3, we will investigate the neuro-immune interactions between MrgprC11+ nerves and asthmatic cytokines and examine if these interactions contribute to airway hyperresponsiveness. These studies will reveal novel neural mechanisms controlling asthma symptoms.
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