Glucocorticoid responsiveness in the lung: impact of inflammation and infection
Professor Alastair Stewart
+61 3 8344 5675
The high level of sensitivity of allergic inflammation to regulation by glucocorticoids (GCs) underlies the therapeutic success of this class of drugs in most cases of asthma, hayfever and urticaria. However, there is a partial resistance to control of severe asthma by GCs and a more profound GC resistance in COPD. Episodes of worsening of asthma and COPD have been explained by patients having an infection of the lower respiratory tract with one or more of several viruses, including respiratory syncytial virus, better known as RSV, Rhinovirus (the common cold) or Flu virus. TGF-β induces resistance to actions of GCs in the respiratory epithelium. Respiratory viruses increase the activity of TGF-β. We will now establish whether blocking TGF-β can restore steroid sensitivity in viral exacerbations of chronic respiratory disease. In this project there are a range of methodologies that you may use including culture of epithelial cell lines and primary epithelium (in air liquid interface culture) obtained from healthy normal and diseased (asthmatic or COPD) airway. In addition, human monocyte/macrophages will be isolated from asthmatics who respond well to steroids, those who respond poorly and from control subjects. Gene expression will be measured by quantitative RT-PCR and RNA-seq; protein expression is measured by western blotting or enzyme-linked immunosorbent assay; Live cell imaging is used to track the translocation of YFP-tagged wild-type and mutated GRs. Gene expression reporter constructs and interventions using transient cell transfection with silencing RNA or small molecular weight chemical tools will assist in implicating specific pathways in virus responses. The results you obtain will guide new approaches to reversing steroid resistance in chronic inflammatory diseases.
This research project is available to Honours students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.
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