The Role of Posttranscriptional Regulation in the Pathogenesis of Allergic Asthm

Asthma is a highly prevalent disease characterized by chronic inflammation, airway remodeling, and mucus production. It involves a complex interplay of the airway epithelium, innate immune system, and adaptive immunity that is still not completely understood. Despite the increasing prevalence of asthma, we still have an incomplete understanding of this disease. Addressing this existing knowledge gap will potentially allow us to develop novel therapeutic strategies for the diagnosis and treatment of asthma.;Posttranscriptional regulation (PTR) has emerged as an essential control system for the regulation of gene expression. PTR mediates the fine tuning of protein expression by effecting changes in mRNA stability, availability, and translational efficiency. MicroRNAs (miRNAs) and RNA-binding proteins (RBPs) are crucial mediators of PTR. In this dissertation, we explored the role of these PTR mediators in the inflammatory pathogenesis of asthma. We demonstrated that miR-1248, a miRNA that is overexpressed in asthmatic individuals, positively regulates IL-5 cytokine expression. We also showed that circulating miRNA expression profiles can be used to diagnose and subtype asthma. Additionally, we established that tristetraprolin (TTP), an RBP, destabilizes the IL-13 mRNA and downregulates IL-13 cytokine production. Finally, we demonstrated that ablating TTP expression in the airway epithelium results in neutrophilic pulmonary inflammation. The studies described in this dissertation address key knowledge gaps in the pathogenesis of asthma. We shed light on the importance of PTR in asthma and demonstrate that PTR-based approaches can be beneficial in the clinical management of asthma.