Project description DEENESFRITPL The role of tyrosine phosphatases in metabolic disorders Emerging evidence indicates that protein tyrosine phosphatases (PTPs) are implicated in insulin and glucose signalling, serving as molecular switches for key events in the development of diabetes. Oxidative stress inhibits PTP activity and is associated with obesity and inflammation. Scientists of the EU-funded METAPTPs project have developed an innovative proteomics approach for quantifying PTP oxidation in metabolic cells of patients with diabetes. Insight into PTP inactivation will help determine the impact of PTP deficiency on cellular responses and diabetes development. Moreover, the project will propose specific antioxidants or diets capable of restoring PTP function and reversing metabolic disorders. Show the project objective Hide the project objective Objective Diabetes mellitus is characterised by hyperglycaemia caused by an absolute or relative insulin deficiency. The global prevalence of diabetes has reached more than 410 million individuals, underscoring the need for novel therapeutic strategies targeting the pathology as a multi-organ disease. Protein tyrosine phosphatases (PTPs) constitute a superfamily of enzymes that dephosphorylate tyrosine-phosphorylated proteins and oppose the actions of protein tyrosine kinases. My previous studies and preliminary data suggest that PTPs act as molecular switches for key signalling events in the development of diabetes, i.e. insulin/glucose/cytokine signalling. Dysregulation of these pathways results in metabolic consequences that are cell-specific. Oxidative stress abrogates the nucleophilic properties of the PTP active site and induces conformational changes that inhibit PTP activity and prevent substrate-binding. I have recently developed an innovative proteomic approach to quantify PTP oxidation in vivo and demonstrated that this occurs in liver/pancreas under pathological conditions, including obesity and inflammation. In this proposal, I aim to fully characterise the activity and oxidation status of PTPs in dysfunctional metabolic relevant cells in obesity and diabetes. Importantly, the crucial role of PTPs make them promising candidates for the treatment of metabolic disorders. I hypothesise that specific antioxidants, diets and/or adenovirus will restore PTP function and ameliorate the metabolic deleterious defects in pre-clinical studies. Over the next 5 years, I aim to:• Identify the major oxidised PTPs in metabolic relevant tissues/cells in both obesity and diabetes.• Determine the contribution of PTP inactivation in cellular responses to metabolic signalling in human samples.• Assess the impact of tissue-specific PTP deficiency on the development of obesity and diabetes.• Test novel therapeutic approaches targeting PTPs to prevent/reverse metabolic disorders. Fields of science natural scienceschemical scienceselectrochemistryelectrolysismedical and health sciencesclinical medicineendocrinologydiabetesmedical and health sciencesbasic medicinepathologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesmedical and health scienceshealth sciencesnutritionobesity Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2018-COG - ERC Consolidator Grant Call for proposal ERC-2018-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Coordinator UNIVERSITE LIBRE DE BRUXELLES Net EU contribution € 1 966 906,00 Address Avenue franklin roosevelt 50 1050 Bruxelles / brussel Belgium See on map Region Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad 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 UNIVERSITE LIBRE DE BRUXELLES Belgium Net EU contribution € 1 966 906,00 Address Avenue franklin roosevelt 50 1050 Bruxelles / brussel See on map Region Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad 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
