Asthma affects more than 300 million people worldwide, but despite the current availability of multiple therapies, many patients remain refractory to standard treatments. Furthermore, specific therapies have been linked to adverse and sometimes life-threatening reactions. Thus, an urgent need for new therapies exists. Asthma is associated with chronic airway inflammation that involves both the innate and adaptive immune systems. While Th2 cells and eosinophils play key roles in the pathogenesis of the majority of asthma cases, recently Th17 cells have been implicated in a subgroup of asthmatics associated with neutrophilic airway inflammation and corticosteroid-resistance. Thus, Th2 and Th17 cells represent potential therapeutic targets in the treatment of asthma. Nuclear hormone receptors (NHRs) are validated anti-inflammatory therapeutic targets. This proposal is based on findings that the NHRs PPAR? and REV-ERB? are expressed in Th2 and Th17 cells, where they attenuate T cell effector function and suppress IL-4 and IL-17A expression, respectively. Since both Th2 and Th17 cells are associated with asthma development and pathogenesis, this proposal will investigate whether PPAR? and REV-ERB? are therapeutically accessible targets to ameliorate airway inflammation and asthma. The goal of Aim 1 is to determine the role of PPAR? in Th2 associated airway inflammation and airway hyper-reactivity (AHR), utilizing wild-type and T cell-specific PPAR? knockout (PPAR? cKO) mice in an ovalbumin-induced AHR model. Furthermore, the pharmaceutical potential of PPAR? will be determined by comparing responses of wild-type and PPAR? cKO mice to the PPAR? ligand rosiglitazone (Rosi), in the AHR model.
In Aim 2, the molecular mechanisms underlying PPAR? and the corepressor SMRT functions in Th2 cells will be characterized. Global transcriptomic and cistromic analyses will be conducted in Th2 cells in the absence or presence of PPAR? ligand and these results correlated to identify direct and indirect PPAR? targets. The goal of Aim 3 is to determine the role of REV-ERB? in Th17-associated airway inflammation and AHR using novel T cell-specific REV-ERB? loss-of-function and gain-of-function mouse models, as well as a synthetic REV-ERB agonist, to test the hypothesis that activating REV-ERB? can ameliorate Th17 cell associated AHR and asthma.
In Aim 4, the molecular mechanism of REV-ERB? and ROR?t interactions in Th17 cells will be dissected by mapping the ROR? and REV-ERB? cistromes to gain mechanistic insight into their global DNA binding activities. These genomic binding maps will be compared with transcriptional outcomes in wild-type and REV-ERB? knockout Th17 cells, with the goal of elucidating the REV-ERB? dependent transcriptional network. The proposed studies will advance the understanding of the molecular mechanisms of PPAR? and REV-ERB? actions in T helper cell subsets, and explore their therapeutic potential in T cell function to ameliorate airway inflammation and asthma.
This proposal is directed at characterizing how nuclear receptors PPAR?, REV-ERB?/? and ROR?t control target genes to regulate T cell function associated with asthma development and pathogenesis. This work is anticipated to provide insights for the development of therapeutically accessible targets to ameliorate airway inflammation and asthma.
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