12-month postdoctoral position in cardiovascular pharmacology, CEA, Saclay
12 months Postdoctoral Scientist (M/F) in CARDIOVASCULAR PHARMACOLOGY AND PHYSIOLOGY
Work location
SiMOs - CEA Saclay- Ile-de-France – France
Main scientific field
Pharmacology et Physiology
Secondary scientific fields
Health, human medicine
Key words
G protein-coupled receptor signalling pathways, beta-arrestin recruitment, internalisation, aqueous diuresis, arterial blood pressure,
Employer
Environment
The CEA is a public research organisation at the forefront of research, development and innovation. The Department of Medicines and Technologies for Health (DMTS) is part of the Frédéric Joliot Institute of Life Sciences. The DMTS comprises 3 departments, including the Molecular Engineering for Health Department (SIMoS). SIMoS focuses on the identification and preclinical development of bioactive molecules, using pioneering technologies in the fields of medical imaging, diagnostic advances and therapeutic innovations. The candidate's project will be carried out at SIMoS in the Experimental and Molecular Pharmacology laboratory, directed by Dr Denis Servent, under the supervision of Dr Catherine Llorens-Cortes.
Scientific project
The project, funded by the French Federation of Cardiology and the Paris-Saclay University (SPRINGBOARD), aims to develop and define the functional role of biased agonists of the apelin receptor (Apelin-R). The Apelin-R is expressed in the brain, kidneys, vessels and cardiomyocytes. Apelin-17 (K17F, composed of 17 amino acids) has a subnanomolar affinity for Apelin-R and by activating its receptor, K17F has aquaretic, vasodilatory and positive inotropic effects. Deletion of the C-terminal phenylalanine of K17F (K16P) does not alter the peptide's ability to inhibit cAMP production and has no effect on diuresis. Conversely, this deletion strongly reduces the peptide's ability to 1) recruit beta-arrestin, 2) induce ApelinR internalisation, 3) reduce blood pressure (BP) or 4) increase left ventricular ejection fraction (LVEF), making K16P a biased agonist favoring Gi protein-coupling versus beta-arrestin recruitment. Our aim is to develop biased agonists of ApelinR that are resistant to enzymatic degradation. Their half-life, the ApelinR signalling pathways that they activate and their in vivo efficacy on diuresis, BP and LVEF will be evaluated. (See the articles cited below on one of the metabolically stable K17F analogues.)
The in vitro part of the project is already well advanced. One of the main tasks will be to measure blood pressure in alert rats after subcutaneous administration of the various metabolically stable apelin analogues and to assess their effects on diuresis, water intake and urinary electrolytes in rats placed in a metabolic cage. For blood pressure measurement, he/she will be able to learn from a member of the laboratory.
Certification in animal experimentation - Project Designer + diploma in experimental surgery are mandatory.
The budget finances a full-time scientist position at CEA, Centre de Saclay, SIMoS, for one year, starting no later than September 2025. A potential prolongation will depend on securing additional funds
This work will be carried out in collaboration with Dr Dominique Bonnet (Equipe Chémobiologie et Pharmacognosie pour la Santé, Laboratoire d'Innovation Thérapeutique - UMR 7200 CNRS-Université de Strasbourg, Faculté de Pharmacie) for the design and synthesis of biased agonists of Apelin-R and with Dr Pierre Couvineau (Equipe Granier-Mouillac: Pharmacologie et biologie structurale des protéines membranaires, Institut de Génomique Fonctionnelle, UMR 5203 CNRS - U 1191 INSERM, Montpellier) for the identification of Apelin-R signalling pathways activated by these agonists.
1.Gerbier et al., 2017 Faseb J; 31:687-700. doi: 10.1096/fj.201600784R
2 Flahault et al., 2021 Front. Pharmacol. 12 :715095. doi.org/10.3389/fphar.2021.715095
3. Flahault et al., 2021 Nat. Commun. 12(1): 305. doi: 10.1038/s41467-020-20560-y
4. Girault-Sotias et al. 2024 Can J Cardiol S0828-282X(24)01258-3. doi: 10.1016/j.cjca.2024.11.034
Teleworking: Occasional
Starting date: Septembre 2025
Profile
Qualifications
Candidates should have a PhD. A background in cardiovascular pathophysiology is recommended. Experience in measuring arterial blood pressure in alert rats will be appreciated. Independence and strong motivation are essential. The position will require skills in physiology, in vitro and in vivo pharmacology, data analysis and scientific communication.
Objectives
Our offer
We are offering the opportunity to contribute to a scientific project bringing together several areas of expertise (peptide chemistry, pharmacology and physiology). The post-doc will benefit from all the laboratory's expertise as well as a large number of core facilities. Our collaborative network will offer many opportunities for professional development. The salary will depend on qualifications and professional experience and is calculated in accordance with CEA scales.
Contact: Dr. Catherine. Llorens-Cortes
c.llorens-cortes@college-de-france.fr
catherine.llorenscortes@cea.fr
Tel: +33 (0)62594880