Impact of the inhibition of NLRP3 inflammasome on blood-brain barrier permeability and neuroinflammation in the context of chronic kidney disease.

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Cognitive impairment is one of the major symptoms in most neurodegenerative disorders, and a frequent late comorbidity of disorders associated with systemic inflammation, such as diabetes and chronic kidney disease (CKD). We recently demonstrated that cognitive impairment is associated with both blood-brain barrier dysfunction and neuroinflammation in preclinical models of CKD.
Microglia are the first-line responders to CNS injury, they mediate immune responses by pattern recognition receptors, including toll-like receptors and NOD-like receptors (NLRs). Especially, NLRP3 triggers inflammasome-mediated neuroinflammation and plays a pivotal role in endothelial dysfunction leading to BBB dysfunction. Thus, NLRP3 may be a viable target to interrupt the pathogenesis of cognitive impairment, however to date, no direct NLRP3 inhibitor has reached clinical development. Bruton’s tyrosine kinase (BTK) is required for NLRP3 inflammasome activation and BTK inhibitors are already approved. The role of the BTK/NLRP3 system in neuroinflammation and BBB disruption in the context of CKD is not known.
The purpose of this preclinical project is to challenge the hypothesis of inhibiting BTK to prevent CKD-related cognitive impairment, via promotion of the microglia-protective polarization. The results of this project will contribute to characterize the involvement of BTK/NLRP3 in CKD-related neurological complications, and may provide innovative therapeutic targets in this context.
In this project, we will perform innovative in vivo isotopic imaging and behavioral assessment in the same animals, which constitute a fantastic opportunity to correlate cognitive outcomes to functional neuroimaging.

Desired profile

We are looking for a highly motivated student with a background in neuroscience and/or biomedical science. The candidate will be integrated into a young and dynamic team closely supervised by the PI ,and will work with an experienced engineer during the whole duration of the project.

Host institution

The candidate will work at the interface between CERIMED and the C2VN, and will be hosted in the CERIMED building on the University campus of la Timone.
The European Center of Research in Medical imaging (CERIMED), is a space of synergies between the different disciplines of preclinical and medical imaging, in close links with the industry. It is a unique platform of partnership and pluridisciplinarity, combining the expertise of doctors, pharmacists, biologists and physicists, to offer significant technological advances in medical imaging.
The C2VN, Center for CardioVascular and Nutrition Research, is a joint research unit under the triple supervision of Aix-Marseille University, INSERM and INRAE. With 5 research teams and 5 technological platforms, the Centre is at the heart of one of the biggest public health issues, cardiovascular diseases and their prevention through Nutrition. It is one of the leading French research centers in this field, both nationally and internationally.

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