Metabolomic approaches to identify pathophysiological biomarkers of stroke

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Studentship strategic priority area:Basic & Clinical ResearchKeywords: Stroke, Metabolomics, transcriptomics, biomarkers, pharmacological inhibitorsGlobally Stroke is second only to coronary artery disease as a cause of death, killing over 6 million people each year. The disease arises as blood flow is occluded to the brain, either due to ischemic stroke (where blood flow is blocked in certain vessels) or hemorrhagic stroke, where vessels bleed. In either case, the part of the brain fed by the damaged vessels ceases to function. Transient ischemic attacks are a form of ischemic stroke but which self-resolve within a few hours or less, thus causing less damage. Therapeutic options to manage stroke are rare. Lack of oxygen is a critical causal effect, but other biochemical changes associated with stroke contribute to damage. These include changes to metabolic pathways, such as the polyamine pathway and increased inflammation, manifesting through pathways such as the kynurenine pathway. Our previous work has shown changes to these pathways as well as the discovery of a novel metabolite, related to trimethylamine N-oxide that are associated with stroke. This project aims to learn more about the nature of these changes, the contribution these metabolites make to stroke related pathology and ultimately whether they may be targeted by new compounds that can be developed towards new therapies for stroke management.Aims:1. To evaluate metabolomics datasets from individuals having suffered a stroke or transient ischemic attack to seek pathways and metabolites associated with the condition2. To probe publicly available transcriptomic databases to determine whether gene transcript changes associate with the metabolic changes identified3. To probe, using mass spectrometry, the structure of a trimethylamine N-oxide (TMO) derived metabolite we have found to be associated with stroke4. To initiate work investigating the potential use of pharmacological inhibitors of metabolic pathways associated with stroke in protecting against the disease