PROJECT SUMMARY Asthma affects >300 million people, with high morbidity and healthcare costs. Improved therapies are needed, because current therapies have adverse side effects and are ineffective in many patients. Asthma pathophysiology involves complex regulatory mechanisms in many different cell types, still little-understood at many levels. This research will test the role of a novel regulatory target in asthma, the orphan nuclear hormone receptor peroxisome proliferator-activated receptor δ (PPARδ). Based on preliminary findings that PPARδ acts within the lung to modulate asthma severity, we will determine if its dysregulation contributes to asthma, test feasibility of its therapeutic targeting, and elucidate key mechanisms. Airway epithelial cells (AECs) are important as both mediators and targets of asthma-related inflammation. Preliminary data suggest that PPARδ is downregulated in AECs of asthma patients and lungs of mice with allergic airway disease (AAD), and that globally downregulating PPARδ exacerbates AAD, whereas increasing PPARδ activity alleviates it. Our overall goal is to elucidate the role of PPARδ in regulating asthma severity and the mechanisms involved. The aims are: 1) to determine the mechanisms underlying induction of PPARδ ubiquitination and degradation by asthma- related cytokines and whether the resulting PPARδ deficiency exacerbates AAD pathogenesis and severity, comparing responses of wild-type AAD-bearing mice with those of novel strains having global or AEC-specific PPARδ deficiency; 2) to test whether treatment with novel PPARδ agonists blocks effects of asthma-related cytokines and agonist-induced or constitutive PPARδ activation ameliorates asthma severity specifically via AECs. These studies will exploit our novel resources including PPARδ KO mice lacking the fetal mortality that has hampered previous studies, a novel mouse strain expressing constitutively active PPARδ specifically in AECs, and PPARδ agonists we developed that are uniquely suited to administration by inhalation, preferred for asthma treatment. Taken together, our results will significantly advance understanding of PPARδ roles in lung biology and disease, and identify a new target for improved asthma therapy.