Description du sujet de thèse

AAV (adeno-associated virus) vectors are among the most widely used gene therapy products today. Their production relies on the use of plasmids transfected into host cells. However, exogenous plasmid DNA is often recognized and repressed by intrinsic cellular mechanisms, reducing bioproduction efficiency.
This thesis aims to identify the host proteins involved in plasmid DNA recognition, transcriptional repression and degradation, in order to better understand the molecular barriers to AAV vector production.
The PhD student will focus on interactions between plasmids and known restriction factors (such as cGAS, IFI16, NP220 or the HUSH complex), and seek to understand their role in plasmid DNA stability and transcription. The objectives of the project are to :
- Analyze the expression of host factors involved in the response to exogenous DNA,
- Identify plasmid-associated proteins using targeted proteomics approaches (PICh),
- Invalidate genes of interest using CRISPR-Cas9 or shRNA to assess their functional impact,
- Design optimized cell lines for improved AAV vector production.
This thesis project combines molecular biology, transcriptomics, proteomics and cell engineering. It is part of an interdisciplinary dynamic involving collaborations with experts in virology, gene therapy and CRISPR technologies.

Contexte de travail

The project is part of the PEPR BBTI program (REPLIBIO project) and will be carried out at the Institute of Human Genetics (IGH - UMR 9002, CNRS and University of Montpellier), a research center renowned for its excellence in fundamental biology, particularly in the fields of genome dynamics, epigenetic regulation, developmental genetics and cellular and molecular pathologies.
The PhD student will be integrated into Monsef Benkirane's lab, and will work in collaboration with two other IGH teams (Philippe Pasero and Jihane Basbous), as well as with external partners, notably the Center for Structural Biology (Marcelo Nollmann's team) and Genethon.
The IGH brings together some 230 staff in 21 research teams, and boasts a stimulating scientific environment with a wealth of expertise and technological platforms. The position involves full-time work in a molecular and cellular biology laboratory, with compliance with safety standards (wearing of personal protective equipment mandatory, training in the use of radioactivity if necessary).

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

Biology research laboratory, work conditions with chemical and biological risk.