BJA/RCoA Non-clinical PhD Studentship

University of Aberdeen

Title
Effect of melatonin and its metabolites on key molecular pathways in sepsis

Amount
£85,751

Scientific Abstract
Sepsis is a dysregulated and highly exaggerated systemic inflammatory response to infection, and it is accepted that oxidative stress and mitochondrial dysfunction are involved in the pathophysiology. Melatonin treatment in animal models of sepsis decreases inflammation, oxidative stress, organ dysfunction and mortality. Effects of melatonin on key redox sensitive signalling pathways likely to be of benefit in sepsis have been described in disease models other than sepsis. Metabolites of melatonin, including both those formed after antioxidant reactions, and those formed after metabolism of oral exogenous melatonin, have similar protective effects to melatonin in cell models, but the molecular pathways involved have not been defined. This project will investigate the effects of melatonin and several key reaction products/metabolites on various plausible signalling cascades involved in inflammatory pathways, using in vitro and ex vivo approaches under conditions of sepsis. The results of this work will contribute to knowledge about the molecular mechanisms of the effect of melatonin its metabolites, notably under conditions of sepsis, and the conditionality of such effects. This information has broad applicability and is crucial to inform proof of concept translational approaches, with a view to future targeted drug development.

Please see the NIAA's position statement on the use of animals in medical research.

Imperial College, London

Title
Cellular interactions and functions of microvesicles in the systemic inflammatory response syndrome

Amount
£90,488

Scientific Abstract
As all previous attempts to treat the systemic inflammatory response syndrome (SIRS) by inhibiting soluble mediators of inflammation have been unsuccessful, there remains an urgent need to identify novel therapies for treatment of critical care patients. Microvesicles (MVs) are cell-derived particles emerging as alternative mediators of inflammation, capable of carrying complex signalling information over long distances. Despite the known ability of MVs to activate or modify the phenotype of target cells in vitro, very little is known about how these processes occur in the circulation during SIRS. We recently found that under inflammatory conditions, monocytes acquire an enhanced ability to interact with, and internalise MVs and that this process took place within the microcirculation of the lungs and liver. Here, we propose to investigate MV uptake under inflammatory conditions using primary human cells and patient samples in vitro, to determine: (1) the key cell types capable of interacting with MVs during SIRS, (2) the importance of MV phenotypic heterogeneity in this process, (3) the molecular mechanisms involved in uptake and internalisation and (4) the responses elicited in target cells. The results generated will help clarify the role of MVs during SIRS and have the potential to identify novel therapeutic targets.

Please see the NIAA's position statement on the use of animals in medical research.