Missions

A post-doctoral position (30 months) is currently available for a collaborative project (co-PI: Pr. Aimin XU, The University of Hong Kong, China), focusing on the role of TMEM33 in fatty liver disease. Candidates should have a keen interest in understanding metabolism, liver physiology and associated disease states. A strong backround in lipid biology and mouse experimentation is required.

Activités

Transmembrane protein 33 (TMEM33) is an endoplasmic reticulum (ER)-localised membrane with poorly-defined functions. Our preliminary result reveals a progressively increased TMEM33 expression in the liver of obese patients with worsening degree of metabolic dysfunction-associated steatotic liver disease (MASLD; NAFLD). In mice with diet-induced MASLD and dyslipidemia, a marked upregulation of TMEM33 occurs predominantly in parenchymal hepatocytes of the liver, whilst TMEM33 knockout mice are refractory to high fat diet-induced dyslipidemia, MASLD and liver injury. Furthermore, siRNA-mediated knockdown of TMEM33 leads to an obvious attenuation of toxic lipids-induced steatosis in both human and mouse hepatocytes. Using RNA-sequencing, we have identified several metabolic pathways altered by TMEM33 deficiency in the mouse liver, including ER stress-responsive chaperones, lipid and sterol metabolism, and immuno-inflammatory responses. Based on these findings, we propose increased hepatic expression of TMEM33 as an important player in initiating and/or perpetuating obesity-induced metabolic complications such as dyslipidemia and MASLD. In this project, we will further evaluate its pathophysiological role in obesity-associated metabolic comorbidities using hepatocyte-specific TMEM33 knockout mice, and will elucidate the molecular mechanism whereby this ER protein disrupts metabolic homeostasis by identifying the direct downstream effectors and interaction partners of TMEM33 in hepatocytes. Additionally, we plan to conduct a proof-of-concept study to explore the therapeutic potential of nanoparticle-mediated hepatocyte-selective delivery of TMEM33 siRNA for the treatment of aforementioned metabolic disorders. The findings from this study are expected to shed new light on molecular pathways linking ER function and
lipid metabolism in hepatocytes, and to provide scientific foundation for future development of novel hepatocytes-targeted therapeutics for precision management of obesity-related metabolic complications.

Compétences

1) Animal experimentation
2) Confocal microscopy
3) Immunology
4) Metabolism
5) Lipid biochemistry

Contexte de travail

Our group takes advantage of a multidisciplinary approach including molecular biology, proteomic profiling, lipidomics, electrophysiology, calcium imaging, and genetic manipulations to investigate the molecular physiology and pharmacology of ion channels and regulators.
Our laboratory is part of the CNRS Institute of Molecular and Cellular Pharmacology located in the City of Nice-Sophia Antipolis (South East of France). This is a leading centre in biology research with state of the art equipment. The city of Nice offers an international dynamic cultural experience combined with a magnificent scenery and easy access to air travel.

Le poste se situe dans un secteur relevant de la protection du potentiel scientifique et technique (PPST), et nécessite donc, conformément à la réglementation, que votre arrivée soit autorisée par l'autorité compétente du MESR.

Contraintes et risques

None

Informations complémentaires

Interested candidates should e-mail a letter of application, including a CV and the names and addresses of at least two referees to:
Eric HONORE (honore@ipmc.cnrs.fr)
IPMC-CNRS
Université Côte d'Azur
660, route des Lucioles
Sophia Antipolis
06560 Valbonne, France
Tel : 33/4/93/95/77/45
http://www.ipmc.cnrs.fr/?page=honore