Project description DEENESFRITPL Role of metabolites on macrophage function Key roles of metabolites are emerging, beyond energy metabolism and biosynthetic processes, in the regulation of immune responses. The EU-funded Metabinnate project will focus on the role of different metabolites with known pro-inflammatory and anti-inflammatory properties that resemble cytokines in function. Researchers will elucidate how metabolic reprogramming controls macrophage activation and function and how these particular metabolites are dynamically regulated. Apart from fundamental knowledge into the interplay of metabolism and the immune system, the project has the potential to identify novel targets for immune modulation as a therapeutic strategy against inflammatory diseases. Show the project objective Hide the project objective Objective The study of the molecular basis to the immune response has for decades concerned receptors and the signalling pathways they activate which lead to immune cell activation. Recently metabolic changes have also been shown to couple to immune effector responses. A shift in appreciation of the role of metabolites beyond energy metabolism and biosynthetic processes has emerged. We have been examining the role of three metabolites in macrophages. We have evidence that two of these, malonyl-CoA and 2-hydroxyglutarate (2-HG) are pro-inflammatory, whilst the third, itaconate, has profound anti-inflammatory effects. In many ways, they mirror cytokines, with malonyl-CoA and 2-HG being akin to pro-inflammatory cytokines, whilst itaconate resembles anti-inflammatory cytokines. The specificity and breadth of the role of these metabolites in macrophages will be mapped in this proposal. For malonyl-CoA we have evidence that it regulates GAPDH, IRG1/CAD (which synthesises itaconate) and the key cytokine IL-1beta. For 2-HG, we will examine the production and actions of its 2 enantiomers, D-2-HG and L-2-HG, focusing on their effect on HIF1alpha and epigenetic regulation. For itaconate we have evidence for a role in Type I interferon modulation, antigen presentation, inflammasome regulation and GAPDH and LDHA (which can produce 2-HG) activities. We also have evidence that OXGR1 is the receptor for itaconate. All of these aspects will be explored in detail. Critically we will also determine the relationship between these metabolites since we have evidence for cross-talk. Their dynamic regulation is likely to be a key aspect of how metabolic reprogramming controls macrophage function. Our studies point to a major shift in our understanding of how intracellular metabolic changes lead to inflammation. The overall aim is therefore to elucidate how metabolic reprogramming controls inflammatory macrophage activation, which may lead to new therapeutic targets for inflammatory diseases. Fields of science medical and health scienceshealth sciencesinflammatory diseasesmedical and health sciencesbasic medicineimmunology Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2018-ADG - ERC Advanced Grant Call for proposal ERC-2018-ADG See other projects for this call Funding Scheme ERC-ADG - Advanced Grant Coordinator THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD, OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN Net EU contribution € 2 484 858,00 Address College green trinity college D02 CX56 Dublin 2 Ireland See on map Region Ireland Eastern and Midland Dublin Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD, OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN Ireland Net EU contribution € 2 484 858,00 Address College green trinity college D02 CX56 Dublin 2 See on map Region Ireland Eastern and Midland Dublin Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
