Mots-Clés
Immunology
Regulatory network
Mathematical model
single-cell
Cellular plasticity
Description
PhD project summary:
Our aim is to develop a new interdisciplinary strategy to identify and model the molecular regulatory networks and cellular interactions controlling the identity and physiological functions of cell types. We will focus on plasmacytoid dendritic cells (pDCs). These immune cells are of interest to the project because their identity and functions are controversial due to their high plasticity. From a methodological point of view, the remarkable plasticity of pDCs poses a unique computational challenge: depending on their tissue microenvironment and state of activation, they express different gene modules, some specific, others shared with dendritic cells or with innate lymphoid cells. This complexity raises fundamental questions about the identity and functions of pDCs, including whether they constitute a unique cell type or belong to the dendritic cell versus innate lymphoid cell family. Recent advances in bioinformatics, notably in single-cell molecular analysis and gene network inference, offer new opportunities to decipher this plasticity. These approaches enable the unsupervised identification of coregulated gene modules, opening the way to a better understanding of the molecular mechanisms that define and maintain the identity of pDCs despite their plasticity, or that control their functions according to their state of activation. To solve this controversy, we are combining the strengths of 2 teams, one expert in immunology (Marc Dalod, at CIML, Marseille) and the other in computer science (Magali Richard, at TIMC, Genoble). Using single-cell characterization techniques, we have established the activation trajectory of pDCs during viral infection. Further analysis of these data will require developing together an algorithmic approach to model the mechanisms governing pDC identity and plasticity. pDCs are a major source of type I and III interferons (IFNs), key cytokines in the antiviral defense of vertebrates. Some of the molecular mechanisms promoting IFN production by pDCs are known; however, this is not sufficient to understand how this function is controlled in time and space. Filling this gap is crucial, as deregulation of the control of IFN production by pDCs contributes to various diseases, including inflammatory or autoimmune diseases such as psoriasis and lupus, or immune dysregulation diseases induced by respiratory or chronic viral infections. The project could therefore open up novel therapeutic avenues for promoting the antiviral role or inhibiting the autoimmune activity of pDCs.
Specific aims:
1. Define the identity of pDCs across tissues, species and conditions, characterizing their regulatory networks compared to those of other immune cell types.
2. Understand the functional plasticity of pDCs, by identifying and characterizing gene modules that vary between successive cellular states of the pDC activation trajectory during viral infection, or according to the tissue or anatomical microenvironment in which they reside.
3. Develop new bioinformatics methods to better identify cell types by finely characterizing the molecular and functional activities of cells in relation to their environment.
Scientific fields and themes:
Bioinformatics / computational biology, mathematical modeling of biological processes, applied to immunology.
Work context:
This position is funded through the CNRS action “80PRIME 2025”, which supports interdisciplinary projects between research units belonging to different CNRS institutes. Successful completion of this project requires interdisciplinary synergy between experimental immunology (Team 1 “Dendritic cells and antiviral defense”, Marc Dalod, CIML unit, Marseille, CNRS Biology Institute) and computer science (Team 2 “Models and Algorithms for Genomics”, Magali Richard, TIMC unit, Grenoble, CNRS Computer Science Institute). None of the objectives of the project can be achieved without this partnership. The interpretation of analyses will draw on the complementary expertise of the 2 teams. Model validation will be based on an iterative process between the partners.
More details in the application form below
Application form: https://emploi.cnrs.fr/Offres/Doctorant/UMR7280-MARDAL-003/Default.aspx?lang=EN