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Identification of novel selective Dopaminergic Receptor 2-beta arrestin antagonist: involvement in schizophrenia treatment

Objective

Schizophrenia is a devastating neuropsychiatric illness that affects more than one percent of the world's population. Drugs acting in part on dopamine D2 receptors (D2R) are commonly used as medication.

Recent evidence has linked dysregulation of Akt-GSK3 signalling pathways with schizophrenia pathogenesis. Since D2R activation has recently be shown to inhibit Akt in the striatum, this new signalling pathway could contribute to the etiology of schizophrenia and thus represents a new interesting research avenue.

The aim of my project is to better characterize this signalling pathway and identify compounds able to act as selective antagonist in order to counterbalancing a defect of this way. For this purpose, I will
- Identify the different partners of this signalling pathway.
- Screen different antipsychotics and their derivatives in order to identify a selective antagonist of the D2R/Akt pathway.
- Study the selective antagonist effects on different mice models of schizophrenia.

In the return host organization, I will apply knowledge and technical expertise I acquired to apelin signalling. The aim of the project is centred around the desensitization/resensitization of apelin receptor and its relationship to a possible heterodimerization between apelin receptor and structurally related receptors such as CXCR4. Then these results will be validated in vivo in a physiopathological model of vascular plasticity.

My project is based on combined in vitro and in vivo approaches to explain the complex role of dopamine receptors, which are of highest relevance for pathophysiological functions in human brain and identify compounds able to treat neuropsychiatric disorders such as schizophrenia.

To accomplish this, I will learn new techniques such as BRET but also signal transduction pathways analysis in mice brain and behaviour, which will complement my previous experience and will be appropriate to establish myself as an independent researcher for my return to France.

Call for proposal

FP6-2005-MOBILITY-6
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Coordinator

INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MEDICALE
EU contribution
No data
Address
CHU Purpan
BP 3048 TOULOUSE
France

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Total cost
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Participants (1)