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We have 2 main aims (graphical abstract):
Aim 1: Integrative analysis of B and T cell subsets, BCR/TCR, and autoAb repertoires in AID. We will deeply phenotype B and T cell subsets in both healthy individuals and AID patients, employing cutting-edge single-cell technologies to map their transcriptomic, proteomic, and epigenetic profiles. This data will be integrated into an immunomics model to better understand the diversity of B/T cell responses across different diseases.
Aim 2: Deciphering myeloid cell responses in target organ homeostasis disruption. Focusing on target organs like the synovial joint, we will explore the interactions between myeloid cells and other immune cells, using advanced techniques including scRNAseq and imaging mass cytometry coupled with systems biology and machine learning. Our goal is to identify myeloid cell subsets and interactions that contribute to disease progression, paving the way for new therapeutic targets.
Our overall objective is to understand disease heterogeneity and identify potential candidates for the development of personalized therapies and innovative strategies targeting tissue homeostasis disruption.
Workpackage 2 (WP2) is built on the complementary expertise of 65 clinicians, researchers, engineers and technicians to propose innovative solutions to restore immune homeostasis in patients suffering from autoimmune diseases (AID). Our consortium is developing cutting-edge biotherapies to selectively target the myeloid cells, T and B lymphocytes involved in AID.
Workpackage 3 (WP3) aims to evaluate the efficacy and safety of therapies based on extracellular vesicles, RNA vectors and CAR-engineered cells in different models (organoids, mathematical models, induced or humanized in vivo models). Longitudinal monitoring of the transcriptomic, metabolic and chromatin organization of CAR-engineered cells will allow the identification of modulated target genes and pathways to predict the immune response.
Workpackage 5 (WP5) is focused on addressing three complex diseases (SLE, RA, and Sclerodermia) through cutting-edge and multidisciplinary technologies, integrating insights from genetics, deep immunophenotyping, transcriptomic and epitranscriptomic analyses, large scale quantitative proteomics, and patient exposure to better stratify the patients.
Multiparametric flow cytometry on PBMCs.
B and T cell purifications for:
• RNAseq Total library
• sc RNA seq VDJ library
Analysis:
• Supervized
• Unsupervized
Single-cell profiling of the patient T and B cells.
Oligoclonality of the TCR and BCR repertoire.
Ag-specific B cell sorting for Immune profiling.
Identification of module of co-regulated genes.
Circulating Biomarkers : Large‐scale quantitative clinical proteomics of patient’s serum.
Multiplexed quantification of chemokines and cytokines.
Autoantigen characterization : Characterization of autoantigens bound to AID-derived serum (LES and Sclerodermia).
Epitranscriptomics : Multiplexed RNA-Modifications quantification.
Multi-omics genomic medicine sequencing :
Long Reads DNA
• SNV and SV analysis
• Methlylation profile
• Long Reads transcriptomics
• Differential expression analysis
• Transcript analysis
Integrated OMICS anaylsis for molecular diagnostic stratification and therapeutic prediction.
Patients’s exposure to:
• Air pollution (remote sensor)
• Water pollution
• Soil contaminants
• Biocontaminants (molds, pollen)
• Infections
• Green, gray, blue spaces
• Diet
• Meteorological variables
• Lifestyle (tobacco, alcohol)
• Occupation
• Socio-economic status
• Etc…
Identification of Biomarkers.
Clustering / Stratification of patients in each AID (RA, SLE, Sclerodermia).
Comparative signature, Identification of sub-population for treatment strategy, Define deregulated pathways and new therapeutic target , in-depth analysis of risk factors, prognostic markers and efficacy of therapeutic interventions, Development of new therapeutic strategies.
Bioproduction of cell or cell-derived ATMPs for clinical applications is a critical part of innovative clinical trials to treat auto-immune diseases. It relies on two cardinal features:
1) a specific cell product, genetically engineered, or modified with antibodies, mRNA or complex culture conditions, meeting specifications that can address unmet clinical applications,
2) a GMP-compliant production that ensures that the end product meets preset specifications, including a robust potency test, and that is produced in sterile, traceable and reproducible fashion. We will complement our bioproduction capacity with private and academic partnerships, including partners of the IHU.
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