Description du sujet de thèse

Amyloid aggregates are associated with many pathologies, like Alzheimers's disease (AD) or Type 2 diabetes (T2DM), respectively involving Ab and amylin. Recent evidence indicates a link between these two diseases, likely mediated by “cross-seeding” processes when one amyloid protein promotes aggregation of another. We have identified the first metal complexes selective for amylin vs Ab fibrils, and here we propose to i) improve their selectivity via rational molecular design, ii) investigate their peptide binding affinities, and iii) exploit their potential as imaging agents for selective MRI or SPECT visualisation of amyloid peptides in ex vivo tissue samples and preclinical models. Depending on the metal complexed, the agents provide detection capabilities in different modalities: MRI (Gd3+), SPECT (111In3+) and/or optical imaging (luminescent Ln3+). These probes will help establish the role of peptide cross-seeding as the link between T2DM and AD. The PhD work will include: (i) synthesis of novel ligands, (ii) characterization of the metal complexes (micelle formation, peptide affinity, MRI properties, etc, (iii) participation to the in vivo evaluation of the novel imaging probes. This doctorate will be funded by ANR within the MASAI project.

Contexte de travail

CBM (UPR 4301) is a CNRS own unit of 140 people where several groups work in synergy at the interface between physics, biology and chemistry. The researcher will be part of the "Metal complexes and MRI" group and will be supervised by the PI of the project. He / She will interact with the other members of the group (3 CNRS researchers, 1 lecturer, 4 engineers, 2 post-docs and 1 PhD students). He / She will have access to the high-performance equipment of the team and of the NMR, MRI and optical spectroscopy platforms in CBM. The work will be performed in close collaboration with the partners of this ANR project (in Toulouse, Grenoble and Oxford).

Contraintes et risques

None

Informations complémentaires

Strong skills in organic synthesis are required.
An experience in poylamine chemistry and knowledge in coordination chemistry will be appreciated.