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Development of the COPD Phenotype:Role of the IL-22/IL-22R1

Institution: University of California, Davis
Investigator(s): Lisa Miller, Ph.D.
Award Cycle: 2017 (Cycle 26) Grant #: 26IP-0045 Award: $299,333
Subject Area: Pulmonary Disease
Award Type: High Impact Pilot Award
Abstracts

Initial Award Abstract

In the United States, chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in adults. Tobacco smoke and other environmental pollutants have been consistently linked to the development of COPD, but there is growing evidence from epidemiologic studies supporting an origin in early life. Specifically, abnormal pulmonary function and airways remodeling are observed at a young age in childhood asthma and longitudinal studies indicate that the normal spectrum of lung function is established in pediatric populations. A recent analysis from the Tucson Children’s Respiratory Study demonstrates that a distinct population of human subjects display a low lung function trajectory from early childhood to adulthood, identifying a cohort of individuals in addition to severe childhood asthmatics and adult tobacco smokers that are predisposed to chronic obstructive disease with increasing age. To date, little is known about antecedent events within the human infant lung that precede and influence development of chronic airways disease later in life. The overall objective of the research proposed in this application is to understand the molecular mechanisms by which environmental tobacco smoke exposure can program the pathogenesis of chronic airways disease in the infant lung. Our laboratory is focused on investigating the normal establishment of innate immune defense and impact of inflammatory injury on reparative processes in pediatric airway epithelium. Using the rhesus macaque monkey as an animal model of lung development, we have reported that the receptor for the cytokine interleukin 22 is significantly reduced in infant rhesus monkey airway epithelium relative to adult airway epithelium, and that suppression of interleukin 22 receptor is regulated by an epigenetic mechanism. This observation is of particular relevance toward understanding the link between mucosal immunity and remodeling of airways in disease, as studies in adult rodent models suggest that the interleukin 22 is important in epithelial repair following influenza infection. Based upon our data and evidence from rodent models, we now hypothesize that environmental tobacco smoke exposure during infancy can persistently dysregulate the reparative response to lung injury via epigenetic regulation of interleukin 22 receptor in airway epithelium. To address our hypothesis, we will use a rhesus monkey airway epithelial cell culture model and a mouse environmental tobacco smoke exposure model to complete our proposed studies.