BTKognition

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. 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 and NLRP3 inflammasome by selective pharmacological agents 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.

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.