ANR POTOMAC : Samy Hadjadj & Mikael Croyal (2022 - 2025)
Samy Hadjadj & Mikael Croyal are the scientific leaders of the ANR-funded project “POst-TranslatiOnal Modifications of Apolipoproteins in diabetes and Cardiovascular risk prediction”.
Abstract
Type 2 diabetes is a major health burden worldwide. The disease is primarily characterized by chronic hyperglycemia and include lipoprotein metabolism disorders, promoting cardiovascular complications. This leads to decrease in both the quality of life and the life expectancy. Since traditional clinical markers cannot fully explain the increased cardiovascular risk of diabetes, the identification of new relevant biomarkers is essential for a better stratification and a better care of the most at-risk diabetic patients. In that context, post-translational modifications of proteins are promising because such structural changes are diverse and sensitive to environmental factors associated with diabetes. Besides, post-translational modifications modify the structure of proteins, change their affinity for biological partners or targets, and act directly on their functionalities. Interestingly, apolipoproteins constitute the structural and regulatory protein component of lipoproteins, responsible for the transport of hydrophobic lipids in the bloodstream. Abnormal apolipoprotein concentrations have been associated with many metabolic and cardiovascular disorders, and plasma apolipoproteins can predict cardiovascular diseases better than plasma lipids. As abnormalities in lipoprotein metabolism are important in type 2 diabetes, we hypothesize that the hyperglycemic environment associated with diabetes overexposes apolipoproteins to post-translational modifications. These structural changes might contribute to critical modifications in lipoprotein functions and turnovers leading to the residual cardiovascular disease risk observed in patients with type 2 diabetes.
Objectives
POTOMAC aims to identify relevant apolipoprotein post-translational modifications via the fundamental approaches of targeted proteomics to functional experiments of biochemistry and cell biology in order to propose a set of new peptide biomarkers related to major apolipoprotein post-translational modifications that will be reliable for large-scale profiling in humans and better stratification of cardiovascular disease risk in patients with type 2 diabetes. Our specific objectives are:
Abstract
Type 2 diabetes is a major health burden worldwide. The disease is primarily characterized by chronic hyperglycemia and include lipoprotein metabolism disorders, promoting cardiovascular complications. This leads to decrease in both the quality of life and the life expectancy. Since traditional clinical markers cannot fully explain the increased cardiovascular risk of diabetes, the identification of new relevant biomarkers is essential for a better stratification and a better care of the most at-risk diabetic patients. In that context, post-translational modifications of proteins are promising because such structural changes are diverse and sensitive to environmental factors associated with diabetes. Besides, post-translational modifications modify the structure of proteins, change their affinity for biological partners or targets, and act directly on their functionalities. Interestingly, apolipoproteins constitute the structural and regulatory protein component of lipoproteins, responsible for the transport of hydrophobic lipids in the bloodstream. Abnormal apolipoprotein concentrations have been associated with many metabolic and cardiovascular disorders, and plasma apolipoproteins can predict cardiovascular diseases better than plasma lipids. As abnormalities in lipoprotein metabolism are important in type 2 diabetes, we hypothesize that the hyperglycemic environment associated with diabetes overexposes apolipoproteins to post-translational modifications. These structural changes might contribute to critical modifications in lipoprotein functions and turnovers leading to the residual cardiovascular disease risk observed in patients with type 2 diabetes.
Objectives
POTOMAC aims to identify relevant apolipoprotein post-translational modifications via the fundamental approaches of targeted proteomics to functional experiments of biochemistry and cell biology in order to propose a set of new peptide biomarkers related to major apolipoprotein post-translational modifications that will be reliable for large-scale profiling in humans and better stratification of cardiovascular disease risk in patients with type 2 diabetes. Our specific objectives are:
- to select relevant post-translational modifications of apolipoprotein associated with type 2 diabetes and to perform mass spectrometry characterization of novel specific peptide biomarkers reflecting these modifications,
- to select the best candidates based on their associations with lipoprotein metabolism dysfunctions determined in vivo, ex vivo, and in vitro,
- to validate candidate peptides in clinical settings including human cohorts and interventional clinical trials,
- to determine the clinical relevance of apolipoprotein post-translational modifications in comparison with the large-scale evaluation of metabolism dysregulation (oxidative stress, inflammation) obtained by complementary approaches. Ultimately, we believe that the combination of the information, namely the concentrations of apolipoproteins and their post-translational modification levels, will help to better understand the mechanisms associated with the disease development and will open new therapeutic avenues.
Mis à jour le 25 July 2022.