Supervisor View Full Details 2nd

• Other

Airway neurobiology

• Medicine

• Respiratory Medicine

My research comprises a comprehensive translational and experimental medicine-based programme developed to investigate the mechanistic principles of acute and chronic cough and to evaluate novel therapies. A prominent theme has been the investigation of novel neuro-inflammatory mechanisms with a specific focus on the expression and functional characteristics of ion channels in human airways.

The study of human airway nerves is hampered by difficulty accessing human tissue and in collaboration with colleagues at QUB (Dr Fionnuala Lundy, Dr Tim Curtis) and using innovative techniques we have overcome this limitation by differentiating adult human dental pulp stems cells and so establishing a novel human ex vivo neuronal model for mechanistic studies on airway neural responses.

Cough is regulated by airway sensory nerves and the development of a sensory neuropathy analogous to that observed in chronic pain states is considered central to the persistence of cough (Chung et al,2013)). How respiratory infections alter neural function is unclear. This project will utilise a novel human neuronal model of peripheral nerves to investigate how respiratory microbes (bacterial and viral) which commonly exacerbate COPD interact with sensory neurons to induce neural injury and neuroinflammation. We hypothesise that such interaction involves the direct activation of pattern recognition receptors (PRR) on sensory nerves and the excessive production of alarmins (sometimes called 'damage proteins') which contribute to neural dysregulation.

Using patch-clamp methodology and calcium imaging we will study the effect of lipopolysaccharide (LPS) endotoxin and viral mimic induced TLR activation. Our work will focus on the activation of TLR 3, 4 and 7 and the production and release of the alarmin, high-mobility group protein B1 (HMGB1), which is considered to have a mechanistic role in neuropathic pain. We will determine whether endogenous ligands such as HMGB1 triggerinflammasome activation in neuronal cells, thereby providing a mechanistic insight into neuroinflammation in COPD. Targeting PRRs or the alarmin pathways may represent novel therapeutic options for patients with troublesome cough associated with infection.

Reference: Chung KF, McGarvey L, Mazzone SB. Chronic cough is a neuropathic condition. Lancet Respiratory Medicine 2013; 1(5): 414-22