Mechanism and clinical validation of glycolytic metabolites as regulators of inflammatory responses in humans

Inflammation has become a very topical area of investigation for the identification of new cardiovascular treatments. ‘Immunometabolism’ or regulation of immunity by metabolic pathways is emerging as a key new regulatory paradigm in immune cells. 

In previous work, the Rena lab has established that immunometabolic regulation occurs in humans in response to the diabetes drug metformin. In the current project, an exciting new collaboration with Dr Ify Mordi will allow us to investigate: (i) a hypothetical mechanism that might underlie these effects and (ii) deduce whether this mechanism is active in humans. In cell work, we have established that increasing glycolytic metabolites to levels achieved by metformin (and also exercise), is sufficient to mediate many of the anti-inflammatory effects of the drug. 

In follow up cell work we will exploit proteomics and available knockouts of key signalling proteins to investigate the mechanism underlying this effect. As part of this work, we will investigate the impact of changes in protein sequence encoded by SNPs in human genes. Next, we will exploit this knowledge to carry out Mendelian Randomisation (MR) to validate that glycolytic metabolites affect inflammation in humans. 

MR uses the random allocation of genetic variation across a population to provide insight into the relationship between a genetically-determine exposure and an outcome of interest. By stratifying large scale genotyped human cohorts MR, we will be able to deduce whether changes in glycolytic metabolites affect inflammation in humans, studying the Neutrophil: Lymphocyte ratio and C-reactive protein. This will definitively establish clinical relevance of these metabolites as inflammatory regulators.