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Do Novel Post-Translationally modified peptides Exacerbate COPD?

RCSI StAR International PhD Programme Research Projects

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Dr Emer Reeves , Dr G McElvaney Applications accepted all year round Competition Funded PhD Project (Students Worldwide)

About the Project

Chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, is a leading cause of disability and mortality. Globally, COPD has become the third leading cause of death after ischemic heart disease and cerebrovascular disease.

Approximately 180,000 people in Ireland have been diagnosed with moderate or severe COPD, and more recently, concerns have been raised over the rate of COPD in Irish women. Cigarette smoking remains thelargest cause of COPD development, but air pollution is a growing contributor, particularly in the developing world. Currently there is no cure and identification of biomarkers and clinical measures that can evaluate respiratory impairment, help prognosticate outcome in patients and identify measures to control symptoms and stabilize health is central to effective and efficient care.

Of major importance, key studies have demonstrated that white blood cells called neutrophils, and neutrophil-derived factors, play a crucial pathological role in the development of COPD. Neutrophils possess both favourable and unfavourable attributes in the airways with advantages involving a role in lung defence against infection, yet disadvantages involving their role in triggering lung tissue damage. Exciting novel data from this laboratory demonstrated that neutrophils express and release an enzyme called Prim2-4. Prim2-4 is the focus of this study and we believe it is a new and significant risk factor for COPD. The overall aim of this innovative study is to investigate whether Prim2-4 can catalyse posttranslational modifications of essential structural proteins of the delicate lung tissue. Specifically, we aim to investigate whether dysregulated Prim2-4 activity leads to changes in the protein folding of essential extracellular matrix (ECM) proteins of the lung.

We hypothesize that Prim2-4 can cause disassembly of the ECM and that this leads to the generation of ECM peptides that can signal through Toll-like receptors on airway epithelial cells and immune cells. We believe this to be of great importance, resulting in increased levels of proinflammatory cytokines, and mucus secretion, thereby amplifying disease severity. Moreover, in this study detection of specific Prim2-4 altered ECM peptides in plasma will be extrapolated as prognostic biomarkers of disease severity in COPD individuals.

In summary, this study will utilize a well-developed clinical framework of COPD patients for the identification of novel changes to ECM proteins as prognostic biomarkers and as potential therapeutic targets in COPDassociated airway disease.

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