Circadian Regulation of Epithelial Immune Reponses in Asthma - Project Summary/Abstract Circadian rhythms of cellular function and physiology are important signals for health, particularly in the lungs and in respiratory diseases. In diseases such as asthma, nocturnal symptoms are a key feature and exacerbations beginning at night from viral infections frequently result in emergency room visits or hospitalizations, but the biology underlying why symptoms and exacerbations occur more often at night is not well understood. Cellular circadian rhythms occur due to intrinsic oscillations of gene expression in a molecular clock that regulates numerous immune genes and pathways implicated in diseases such as asthma. Prior research in mice has indicated that the molecular clock function in airway epithelial cells is important in regulating innate epithelial immune responses to viral infections. However, investigation of circadian regulation in human cells and in clinical diseases such as asthma has been limited. The research proposed in this project will address a current gap in knowledge of circadian regulation in human airway and lung diseases. The project will use an existing biorepository of primary human airway epithelial cells differentiated to an organotypic state at an air-liquid interface from healthy donors and donors with pediatric asthma. Aim 1: Measure viral replication and airway epithelial innate immune responses to human rhinovirus infection in AEC cultures in relation to cellular circadian time. Aim 2: Compare the pattern of circadian cyclic gene expression of innate immune pathways in the airway epithelium of children with asthma and healthy children. Aim 3: Characterize the impact of circadian disruption on epithelial immune responses to infection. The proposed studies will identify epithelial immune pathways under circadian regulation in human airway epithelial cells that can lead to novel therapeutic strategies in the treatment of viral infection and asthma through a circadian biology informed approach. Dr. Powell’s career development plan builds on his background in molecular and cellular biology and clinical expertise in pulmonary and sleep disorders to add training in epithelial innate immunity and viral studies using mechanistic translational approaches, developing expertise in circadian bioinformatics, and methods for molecular manipulation of the core circadian clock in primary human airway epithelia. The K08 award is well- structured to make maximal use of the extensive resources at Seattle Children’s Research Institute and the University of Washington while leveraging the expertise of a mentorship team comprising experts in airway biology, circadian biology, circadian regulation in pulmonary disease, and bioinformatics. The award will lead Dr. Powell to a productive, independent career as a physician-scientist investigating circadian biology in human lung diseases to guide novel therapeutic development.
