Description du sujet de thèse

Vascular calcification (VC) involves the abnormal accumulation of calcium-phosphate hydroxyapatite crystals within the tunica media of arteries and is one of the strongest predictors of cardiovascular disease and mortality in the general population. VC is commonly associated with aging, diabetes, and chronic kidney disease but also with rare diseases such as pseudoxanthoma elasticum (PXE). The pathophysiology of VC is not fully understood and none of the therapies tested to date have clearly prevented VC. The development of VC is a complex cell-driven process balanced between pro- and anti-calcifying factors. Recently, reduced circulating levels of pyrophosphate (PPi, the principal physiologic inhibitor of hydroxyapatite deposition in soft connective tissues) have been proposed to be a unifying pathophysiological mechanism for acquired and genetic diseases linked to ectopic calcification. Recently, zinc has emerged as a critical regulator of VC but the mechanisms underlying this regulation are poorly understood. In view of preliminary but consistent findings, we hypothesize that zinc affects PPi homeostasis and, through this pathway, prevents ectopic calcification.

The aims of the thesis project are (i) to decipher the effect of zinc on PPi homeostasis in vitro in several cell types involved in PPi homeostasis and calcification (hepatocytes, kidney cells, arterial smooth muscle cells, endothelial cells). Specifically, we aim to determine whether Zn affects PPi-producing enzymes, PPi-degrading enzymes, or membrane proteins involved in the efflux of ATP or PPi. We will also determine whether Zn reduces calcification of dermal fibroblasts derived from PXE patients and if it is accompanied by increased extracellular PPi concentration. (ii) to study the link between circulating Zn, PPi and VC in a cohort of PXE patients (CHU Nice) and we will investigate if oral Zn administration results in a time-dependent rise in plasma PPi levels in PXE patients in a pharmacokinetic study.
This thesis project will improve our understanding of the pathophysiological mechanisms of VC and will open new perspectives for developing new strategies for treating PXE patients, such as restoring physiological PPi levels with zinc supplementation.

Contexte de travail

Team Ion Channels and Biomineralization belongs to Laboratoire de Physiomédecine Moléculaire (LP2M) is part of the CNRS, the major research institution in France, and Université Côte d'Azur “Université d'Excellence”. The laboratory is located at the Faculté de Médecine in the center of the city of Nice, in the French Riviera. The laboratory offers high quality scientific environment with strong interactions with clinicians and access to the required platforms.

Contraintes et risques

Possible work in isolated conditions
Handling biological samples.