Thèse Approches Chémobiologiques pour la Toxicologie des Terres Rares chez l'Humain H/F

Doctorat_Gouv

Établissement : Université Grenoble Alpes
École doctorale : CSV- Chimie et Sciences du Vivant
Laboratoire de recherche : Systèmes Moléculaires et Nano Matériaux pour l'Énergie et la Santé
Direction de la thèse : Pascale DELANGLE ORCID 0000000285469080
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-04-09T23:59:59

L'utilisation technologique des lanthanides s'est intensifiée dans des domaines aussi divers que les énergies renouvelables, l'informatique et la médecine. Leur utilisation croissante pose la question de leur impact sur l'environnement et la santé humaine. Cependant, peu d'études existent sur leur toxicité éventuelle et les mécanismes moléculaires qui la sous-tendent. Nous proposons une approche pluridisciplinaire pour répondre à ces questions, et notamment : (i) identifier les protéines impliquées dans la réponse cellulaire à l'exposition aux lanthanides ; (ii) identifier les protéines interagissant avec ces ions métalliques, en utilisant des outils chémobiologiques développées au laboratoire. Nous déterminerons ainsi les partenaires d'interaction de ces métaux critiques, leur effet sur les organismes vivants et les caractéristiques clés qui leur permettent de lier le métal. Nos résultats permettront d'étendre nos connaissances sur la toxicologie de ces métaux, peu étudiée, et d'informer les politiques de protection environnementale et humaine. Sur le long terme, la compréhension des mécanismes moléculaires des interactions métal-vivant permettra l'émergence de stratégies bio-inspirées pour leur extraction, leur recyclage et leur (bio)remédiation.

The increasing use of lanthanides (Ln) in technologies raises the question of their impact on environment and human health. However, the potential toxicity of these metal ions, and its underlying molecular mechanisms, are still little known and rarely investigated in human cell models. The goal of the PhD will be to investigate the human cells response to exposure to Ln ions, and to systematically identify the proteins involved in this response, using a set of chemical and biological tools. In particular, we want to address the following questions: which protein networks are activated or deactivated following Ln exposure? Do Ln ions affect phosphorylation of proteins? Which proteins are directly interacting with Ln ions?

1) Assessing the cellular response to three representative Rare Earth elements (lanthanides, Ln) in human cells (bone, liver, kidney).
2) Understanding the molecular mechanisms underlying the response to Ln(III) ions, in particular by identifying their interacting proteome (lanthanoproteome).

1. Cell response to Ln(III) exposure
Cell response to three selected Ln ions will first be assessed using a range of assays (cytotoxicity, genotoxicity, oxidative stress), in relevant exposure cell models (in particular, hepatocytes). The proteins involved in this cell response will then be identified using proteomics approaches. In biological media, Ln are mostly present as Ln(III) ions, which interact strongly with carboxylates and phosphates. Phosphoproteomics experiments will thus be performed, to examine the interplay between Ln(III) and protein phosphorylation.
2. Identification of Ln(III) binding proteins
In addition to identify proteins which levels are modified upon Ln(III) exposure, it is also important to identify proteins binding to Ln(III). However, identifying protein-Ln interactions remains challenging due to their transient character. A common strategy consist in immobilizing the metal ion of interest on a solid support, which is then used to enrich metal-affine proteins. In addition, metal-responsive probes are currently developed in our team to label lanthanide-interacting proteins in mammalian cells. The current project will
build on these results and seek to optimize these probes for use in a complex biological environment. Both strategies will be implemented, and the enriched proteins will be identified by (phospho)proteomics. We will finally validate and investigate the interactions of Ln with a few identified proteins. These proteomic data, through the identification of Ln-binding proteins, will provide a better understanding of Ln toxicology, and inspire new strategies for their remediation.