Pharmacology and Therapeutics - Theses

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The impact of cyclic AMP elevating agents on steroid resistance

Bao, Cheng ( 2016)

Glucocorticoids are the most effective treatment for long-term control of asthma. However, a subset of patients require a much higher dose of glucocorticoids to achieve the effect of of treatment, and even the ceiling glucocorticoid response in those patients is lower. The insensitivity to glucocorticoid is termed glucocorticoid resistance. Many factors have been discovered to impair glucocorticoid response, including transforming growth factor beta (TGF-β). The research aimed to elucidate the effect of cAMP-elevating agents on TGF-β impaired glucocorticoid response. The experiments were mostly conducted in cells. GRE-SEAP assay was used to measure agonist activity and real-time polymerase chain reaction was used to measure the expression level of related genes. The results showed that compounds which induced higher cAMP level enhanced glucocorticoid response; whereas the repression caused by TGF-β and whether the repression can be attenuated by cAMP-elevating agents varied between genes and cell types. We attempted to investigate the effect of cAMP-elevating agents on glucocorticoid receptor (GR) translocation in airway epithelial cells, but GR predominantly distributed in the nucleus at the basal level and thus how cAMP influence GR translocation was not confirmed yet. A pilot study of glucocorticoid resistance in human nasal polyps is also included.