Détails de l'offre
- Type de poste: PhD/Doctorat
- Secteur : Public
- Localité : France
- Limite de candidature : 10/06/2022
- Profil de poste:
Recherche et innovation
- Domaine(s) :
Microbiologie et Immunologie, Autre
Funded by the France-Arizona Institute for Global Grand Challenges, this PhD will be performed in tight collaboration with the group of Michael Marty at the University of Arizona (Tucson, USA). At the IPBS, the PhD student will be co-supervised by Julien Marcoux (Odile Schiltz team) and Etienne Meunier.
The global COVID-19 pandemic has revealed the enormous societal danger of viral diseases, and the emergence of antibiotic resistant “superbugs” could overturn a century of progress in fighting bacterial pathogens.
To combat these ongoing threats, we need new strategies for developing drugs and new insights into microbial biology. This collaborative project seeks to address these grand challenges by developing new technologies to study interactions in viral and bacterial membranes, which will allow us to address critical roadblocks in understanding pathogen biology and provide new strategies for targeting resistant and emerging pathogens.
Every cell (including bacteria, parasites, and fungi) and many viruses are surrounded by a lipid bilayer membrane that encapsulates them in a protective shell. Because the integrity of the membrane is essential for cell survival, a wide range of organisms have evolved natural defenses against pathogens that seek to disrupt bacterial or viral membranes by opening small holes in the lipid bilayer.
These antimicrobial peptides (AMPs) and antiviral peptides (AVPs) play an important role in the innate immune system and may be more effective at targeting antibiotic resistant bacteria or vaccine-resistant variant viruses because they broadly disrupt bacterial/viral membranes rather than targeting specific proteins or pathways. However, their mechanisms of action are poorly understood and effective technologies for studying formation and interactions of AMPs/AVPs within bacterial/viral membranes are lacking.
This project seeks to address fundamental questions about how membrane pores assemble. Understanding the mechanisms of pore formation will enable development of efficient drugs to target resistant bacteria and viruses. Additionally, the technologies we develop to address these challenges will have broad utility in studying membrane proteins and transmembrane peptides involved in a wide range of diseases, including cancer and neurodegenerative diseases.
Existing technologies to study pore-forming peptides have generally fallen into two categories. First, are high-resolution techniques, such as X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy provide an atomic picture of the molecular structure. Although highly detailed, these techniques are ineffective for polydisperse proteins and peptides that do not have a single structure but rather exist in a range of conformations.
AMPs and AVPs that we seek to study are often too polydisperse for these high-resolution techniques. Second, there are lower resolution techniques that are more amenable for polydisperse complexes but only provide limited details on the molecular mechanisms of AMP/AVP complexes such as the average size of the pore complex. We are currently developing original intermediate tools between these two regimes that provide rich structural information on polydisperse complexes.
The overarching goal of this project is to develop detailed structural characterization tools for polydisperse complexes and use them to study AMPs/AVPs. We will combine unique mass spectrometry (MS) tools from Dr. Michael Marty’s Lab at the University of Arizona (UA) and Dr. Julien Marcoux’s Lab at the Institute of Pharmacology and Structural Biology (IPBS-CNRS) of Toulouse. The Marty Lab has been developing native MS (nMS) to characterize intact lipid nanoparticles called nanodiscs (NDs).
By measuring the mass of NDs with embedded AMPs, they can precisely quantify the number of peptides assembled into the complexes inside nanoscale lipid membranes but cannot distinguish pore assemblies from pre-pore intermediates. To address this limitation, the Marcoux Lab has been developing hydrogen-deuterium exchange (HDX) MS methods to study the dynamics of protein complexes and recently applied them to membrane proteins in detergent and NDs.
HDX-MS will thus reveal how the complexes determined by nMS are folded in the membrane to demonstrate pore formation. It will also provide crucial information regarding the stability of the pores in different lipid environments, rationalizing the specificity of pore-forming peptides. Combining these two complementary technologies will provide new insights into AMP and AVP systems.
On top of MS-based experiments, the student will perform virulence assays in the lab of Etienne Meunier and molecular dynamics simulation in collaboration with the team of Matthieu Chavent (IPBS).
This project is funded by the France-Arizona Institute for Global Grand Challenges.
Web site for additional job details: https://emploi.cnrs.fr/Offres/Doctorant/UMR5089-JULMAR-003/Default.aspx
Required Research Experiences
Application Deadline: 10/06/2022 23:59 – Europe/Brussels