PhD position on copper chelators in Alzheimer's disease (M/F)

Job Description

Thesis Subject

Alzheimer's disease (AD) is the leading cause of dementia worldwide. To date, there is still no cure for this disease. Between 2003 and 2012, more than 200 molecules targeting the causes of the disease, rather than just its symptoms, failed at various stages of clinical trials. In this context, there is an urgent need to develop new research tools to aid in the design of effective drug candidates.
Although the mechanisms underlying this complex disease are not fully understood, there is a general consensus attributing the development of AD to the amyloid cascade. This process, is based on the production of a peptide called β-amyloid (Aβ) and its accumulation, leading to the successive extracellular formation of oligomers, fibrils and amyloid plaques. Such aggregates are thought to trigger various pathological events associated with AD.
Furthermore, dysregulation of metal ion homeostasis, particularly for copper and zinc ions, is also linked to the amyloid cascade process. Numerous pieces of evidence have linked the high toxicity of Cu bound to Aβ to its ability to promote the oxidative stress observed in AD via the catalytic production of toxic reactive oxygen species (ROS) (Encyclopedia of Inorganic and Bioinorganic Chemistry, 2018, doi.org/10.1002/9781119951438.eibc2635). For these reasons, Cu is considered a therapeutic target of interest. The removal of Cu from the Cu-Aβ complex by ligands (L) is a particularly promising approach because it combines the advantages of having an impact on (i) the production of ROS, (ii) the formation of toxic aggregates (Inorganic Chemistry, 2019, 58, 20, 13509-13527) and (iii) copper homeostasis.
It is in this context that the proposed thesis topic fits. Original ligands (L) (Inorganic Chemistry, 2024, 63, 2340-2351), capable of removing copper from Cu-Aβ and stopping the associated ROS production (Figure 2) were synthetized in the team. The work of the recruited pH D student aims to characterized the complexes made by L and metal ions through analytical chemistry. Furthermore, the ability of L to remove copper from Cu-Aβ and stop the associated ROS production will be studied in vitro (in test tubes) and on model cell lines (in vivo). The experiments will focus on cultured cells to analyze how L penetrates cells, modifies Cu distribution, and influences cell viability and inflammation markers. The improvement in cell survival in the presence of L and Cu-Aβ will be studied using various techniques.
The candidate must be motivated, persevering and eager to work at the interface between chemistry and health in a multidisciplinary environment. The candidate must hold a Master's degree (or equivalent) in chemistry/cellular/molecular biology, biochemistry, pharmacology or related disciplines. A keen interest in therapeutic chemistry and the chemistry-biology interface is essential.

Your Work Environment

The thesis work will be carried at the Coordination Chemistry Laboratory (LCC) in Toulouse il the 'Alzheimer, Amyloids and BioInorganic Chemistry' team headed by Dr. Christelle Hureau and in collaboration with the Institute of Cellular and Integrative Neurosciences in Strasbourg, within Dr Nicolas Vitale's team for the cell experiments. These experiments will then be implemented at the LCC. The thesis work will be supervised by Dr Charlène Esmieu, and Dr Christelle Hureau.

Compensation and benefits

Compensation

2300 € gross monthly

Annual leave and RTT

44 jours

Remote Working practice and compensation

Pratique et indemnisation du TT

Transport

Prise en charge à 75% du coût et forfait mobilité durable jusqu’à 300€

About the offer

About the CNRS

The CNRS is a major player in fundamental research on a global scale. The CNRS is the only French organization active in all scientific fields. Its unique position as a multi-specialist allows it to bring together different disciplines to address the most important challenges of the contemporary world, in connection with the actors of change.

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