Nome e qualifica del proponente del progetto: 
sb_p_1486295
Anno: 
2019
Abstract: 

Epigenetic deregulation has a role in type 2 diabetes mellitus (T2DM) etiology as well as in the development of its complications. Recent studies show that hyperglycemia can induce both global and site-specific demethylation but the underlying molecular mechanisms are under investigation. Our previous research suggests a role of PARP-1 (polyADP-ribose polymerase) in controlling both expression and catalytic activity of Ten-eleven Translocation (TET) enzymes, which are responsible for catalyzing DNA demethylation by converting 5 methyl-cytosine (5mC) into cytosine, through different oxidized intermediates, namely 5hmC, 5fC and 5caC (5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine).
Our preliminary data (funded by Ateneo 2018) reveal variation both in DNA methylation state and in cellular PARP activity in PBMCs (Peripheral blood mononuclear cells) from a cohort of T2DM patients. In particular, PBMCs from patients with high glycated hemoglobin (HbA1c>7.5%) accumulated iteratively oxidized forms of methylated cytosines (5hmC and 5fC) versus patients with low HbA1c and healthy subjects. In parallel, we observed a significant gain in PAR (polyADP-ribose) level, suggesting that PARP1 activation, induced by the oxidative stress, may cause the block of the demethylation cascade.
This evidence opens up to the hypothesis that PARylation may have implications on the TET enzyme machinery and DNA demethylation. In the present project, we aim to test the hypothesis that the altered DNA methylation pattern, observed in patients with poor glycemic control (HbA1c>7.5%), depends on PARP-1 activity. The understanding of the mechanism controlling 5hmC and 5fC accumulation in T2DM is important, since restoring the control of DNA demethylation cycle promises beneficial effects. In this context, the use of PARP inhibitors may be therapeutically relevant.

ERC: 
LS2_5
LS4_5
Componenti gruppo di ricerca: 
sb_cp_is_2067709
sb_cp_is_1851505
sb_cp_is_1894100
sb_cp_is_2010616
Innovatività: 

Highlights
Relevance: the project points out the molecular links between uncontrolled diabetes and epimutations underlying aetiology, progression and development of complications in T2DM.
Innovativeness: PARylation may be considered a key process able to transduce the insults due to poor glycemic control into variations of the epigenetic code, paving the way to the exploitation of PARP inhibitors in diabetes management.
Originality: PARylation could constitute a link between oxidative stress, typical of a condition of poor glycemic control, and epigenetic deregulation.
Feasibility: The project will unite expertise in PARylation and DNA methylation with expertise in clinical medicine of diabetes. The proponents have the right background and possess the basic equipment to address the experimental aims of the project. The recruitment of most of patients involved in the study has been already accomplished.

The hyperglycaemia-driven overproduction of reactive oxygen species and oxidative stress are the major biochemical abnormalities underlying diabetes pathogenesis and complications and have been proposed as the primary mediators of 'glucotoxicity'. In this process, the ROS-mediated activation of PARP1 has been proposed to trigger cell death and impairment of glucose disposal. More recently, it was found that glucotoxicity generates permanent changes of the expression of genes associated with the control of glucose homeostasis through epigenetic regulatory mechanisms. This finding offers an elegant explanation of the phenomenon of "metabolic memory", which accounts for the correlation between transient/chronic poor glycaemic control and the irreversible progression of diabetic complications. In this context, by investigating the link between PARP activation and HG-induced DNA methylation defects, this project aims to collect initial evidence that may form an understanding for the mechanistic basis of the emerging connection between defective glucose metabolism and epigenetic modifications of chromatin in diabetes.
Further, far-reaching relevant implications of this research include the use of PARP inhibitors as new therapeutic drugs in the management of diabetes by delaying some complications thus improving the patient outcome. In addition, PARs could be exploited as indicators of peripheral DNA damage and cellular stress and they would represent new biomarkers for the follow-up monitoring of the diabetic patient

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Codice Bando: 
1486295

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