Phd contract in the field of Medical sciences financed for three years by the University of Clermont Auvergne

Functional characterization of a new variant of the bile acid nuclear receptor FXRα by in vitro and in vivo approaches.

The nuclear bile acid receptor FXRα acts as an inducible transcription factor whose function isinvolved in the regulation of liver activity through its action on bile acid, carbohydrate and lipid metabolism. To date, the four described forms of FXRα that arise from splicing of transcripts produced from the two promoters of the NR1H4 gene differ in their tissue expression profile and target gene repertoires. These observations suggest an isoform-specific regulation of certain functions of FXRα which has become a potential therapeutic target in the treatment of many diseases since its loss of functionis often associated with metabolic disorders (steatosis, diabetes, obesity) and cancer development. Our recent work has identified a new splice variant of FXRα lacking half of its DNA binding domain which raises questions about its physical and functionalinteractions. The objective of the project is to explore the biological functions of this variant by incorporating its sequence into mouse hepatocytes in vivo, and then to study its molecular and genetic interactions using molecular biology and functionalgenomics approaches. These data will contribute to the evolution of the ongoing team's i-Site Emergence project, which will aim in its pursuit to discriminate the specificity of action of alternatively spliced variantsofFXRα.

Garciaet al. (2018) Nuclear receptor metabolism of bile acids and xenobiotics: a coordinated detoxification system with impact in health and diseases. Int J Mol Sci.19(11): 3630.