Characterisation of novel inhibitors of vascular injury due to inflammation

Myeloperoxidase (MPO) is a haemoprotein that is highly expressed in neutrophils and is secreted during injury and inflammation to assist in host defence reactions by producing antimicrobial reactive oxygen species. However, in pathological conditions persistent production of MPO-derived oxidants contributes to tissue damage. Elevated MPO and its oxidants are markers of inflammation, and elevated MPO levels predict adverse outcome in patients with heart disease. The identification and characterisation of drugs which can inhibit the actions of MPO and scavenge HOCl is clearly desirable.

This project will use a novel in vitro model of vascular dysfunction involving MPO and porcine isolated coronary arteries to determine the potential of hydrogen sulphide (H2S)-releasing compounds as therapeutic agents in cardiovascular disease. Arteries will be incubated with MPO followed by an assessment of their vasomotor function using a pharmacological approach. H2S donors, including a novel compound, GYY4137, which acts as a slow-releasing H2S donor, will be investigated as potential vasoprotective agents. Their effects will be compared with those of known MPO inhibitors. Direct vasomotor actions of the compounds will be investigated. H2S-mediated inhibition of MPO activity will also be measured using a biochemical assay. This project is part of a broader research interest within the laboratory on the effects of H2S in the cardiovascular system. The student will be trained in all aspects of the research.

The University of Nottingham is one of the world’s most respected research-intensive universities, ranked 8th in the UK for research power (REF 2014). Students studying in the School of Life Sciences will have the opportunity to thrive in a vibrant, multidisciplinary environment, with expert supervision from leaders in their field, state-of-the-art facilities and strong links with industry. Students are closely monitored in terms of their personal and professional progression throughout their study period and are assigned academic mentors in addition to their supervisory team. The School provides structured training as a fundamental part of postgraduate personal development and our training programme enables students to develop skills across the four domains of the Vitae Researcher Development Framework (RDF). During their studies, students will also have the opportunity to attend and present at conferences around the world. The School puts strong emphasis on the promotion of postgraduate research with a 2-day annual PhD research symposium attended by all students, plus academic staff and invited speakers.