Molecular mechanisms underlying persistent effects of early life exposure on lung function and remodeling

Project Summary/Abstract Exposures to aeroallergens and air pollution remain prevalent in young children, whose lungs are rapidly devel- oping and growing. Such exposures may increase the susceptibility to developing asthma and other lung dis- eases. Previous studies in non-human primate models of early life exposure, asthma and recovery showed that co-exposure to ozone and house dust mite (HDM) between 1 month to 6 months of age leads to hallmarks of asthma phenotypes in infant rhesus macaques (6-month cohort). Interestingly, following removal of exposures, exposed animals continued to have abnormal lung growth and airway hyperresponsiveness when they reached adolescence (36-month cohort). These long-lasting effects of early life exposure could be due to the epigenetic imprints of exposures on gene expression. Although relationships between early-life exposure, epigenetic mech- anisms, and persistent phenotypic changes in the lung have been supported by studies in humans and animal models, direct evidence supporting causal relationships from a model resembling human early life development is lacking and remains as a significant research gap. Our long-term goal is to understand the respiratory health effects of air pollution and aeroallergen and design mechanistically-driven novel therapeutics for lung diseases. The objective of this proposal is to characterize the impact of postnatal early-life exposure to HDM and O3 on the lung epigenome and explore a mechanistic link between these changes and alveolar development and air- way remodeling. Leveraging collected samples from established models and cutting-edge comprehensive epige- nomic analyses, we will test the hypothesis that postnatal early-life exposure to ozone and HDM alters the pulmonary epigenome and leads to changes contributing to persistent airway remodeling and abnormal lung development. Aim 1 will determine the epigenetic mechanisms responsive to early-life exposure to ozone and aeroallergen in the 6-month cohort of rhesus monkeys. Epigenetic changes induced by exposures and associ- ated with phenotypic changes will be identified from lung tissues collected following the last exposure in rhesus monkeys aged 6 months, and gene regulatory mechanisms underlying these changes will be inferred and pre- dicted. Aim 2 will determine the epigenetic mechanisms underlying continued abnormal lung function and de- velopment following early life exposures in the 36-month cohort. Lung tissues will undergo the same analyses as in Aim 1, and differences between the exposed and control groups will be determined. Data from Aims 1 and 2 will also be integrated to provide a better understanding of the longitudinal impact of early exposures. Comparative analyses to human asthma and mouse models of asthma may futher support the utility of non- human primate models of asthma. Leveraging existing tissues from established models, this exploratory and developmental R21 will provide new insights into the mechanisms of postnatal early-life lung development and the impact of early-life exposure on airway and lung remodeling and may provide new preventative and thera- peutic targets for lung diseases with an early life origin.