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

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

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

Address

Avenue Franklin Roosevelt 50
1050 Bruxelles

Belgium

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 966 906

Beneficiaries (1)

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UNIVERSITE LIBRE DE BRUXELLES

Belgium

EU Contribution

€ 1 966 906

Project information

Grant agreement ID: 817940

Status

Ongoing project

  • Start date

    1 April 2019

  • End date

    31 March 2024

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 966 906

  • EU contribution

    € 1 966 906

Hosted by:

UNIVERSITE LIBRE DE BRUXELLES

Belgium