Pulmonary vagal sensory neurons in chronic lung disease - PROJECT SUMMARY Preterm infants are born with immature lungs and immature neural control of breathing. They rely on supplemental oxygen therapy (hyperoxia; HX). Though necessary for survival, they require HX which progressively damages the lungs and causes bronchopulmonary dysplasia (BPD), the most common respiratory complication among preterm infants. Infants with BPD have worse neural control of breathing (nCOB) than age- matched non-BPD infants, suggesting HX dose and/or duration contribute to worse breathing control. With HX used to varying amounts and durations among nearly all preterm births and with BPD infants having a greater risk for adulthood respiratory health complications, understanding the dose- and duration-dependent effects of HX on breathing acutely and chronically remains a critical knowledge gap in the management of millions of preterm infants born each year and future adults who had BPD. Moreover, the underlying mechanisms contributing to dysfunctional nCOB in BPD (and other lung diseases) are unknown. Compelling published and preliminary data suggest a major role of pulmonary vagal sensory neurons (PSNs). PSNs make up the lung- brain neural axis. They provide sensory input that critically modulates breathing. Moreover, molecularly distinct PSNs have unique innervation targets within the lungs and brain, reflecting their functionally distinct influences on breathing. However, their role in dysfunctional nCOB in response to varying doses and durations of neonatal hyperoxia remains unknown. To address these knowledge gaps, a novel mouse model will be employed to test the dose and duration-dependent effects on breathing and the functional roles and structure of 3 distinct PSNs via 3 Cre-driver mouse strains. In Aim 1, comprehensive respiratory physiological measurements will be made acutely and chronically with chemogenetics to inhibit PSNs reversibly. This will address the short and long-term impact of HX dose and/or duration and assess the role of PSNs in the nCOB. In Aim 2, optogenetics will be used to define PSNs' role in ventilatory responses to common respiratory stimuli and how HX alters these roles. In Aim 3, structural analyses of PSN innervation into the lungs and the brain will be completed using combinations of cell sorting, single nuclear RNA Sequencing, and viral tracers. Completion of these Aims will address the novel hypothesis that in a dose and/or duration-dependent manner, HX functionally and structurally alters PSN lung-brain axes, causing short and long-term nCOB changes. Results will impact the clinical management of preterm infants such that they can live longer and healthier lives, expand the understanding of PSNs in dysfunctional nCOB in lung diseases and establish new mechanisms for developing therapies to improve the nCOB for which too few exist. These deliverables align with NHLBI’s mission statement related to preventing and treating lung diseases, stimulating basic discoveries, and driving results to improve clinical practice.
