CORDIS - EU research results
CORDIS

PROTEIN TYROSINE PHOSPHATASES IN METABOLIC DISEASES: OXIDATION, DYSFUNCTION AND THERAPEUTIC POTENTIAL

Project description

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.

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.

Host institution

UNIVERSITE LIBRE DE BRUXELLES
Net EU contribution
€ 1 966 906,00
Address
AVENUE FRANKLIN ROOSEVELT 50
1050 Bruxelles / Brussel
Belgium

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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
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Total cost
€ 1 966 906,00

Beneficiaries (1)