ESPCI web site
SMBP Laboratory (Biological Mass Spectrometry and Proteomics), LPC CNRS-UMR8249
SMBP - ESPCI Paris - 10 rue Vauquelin - 75005 PARIS
LABORATORY DESCRIPTION :
SMBP’s core research activity is developing new strategies for analyzing biological macromolecules and, more specifically, the study of proteins. The SMBP laboratory at ESPCI has an analytical platform specialized in proteomics, which is nationally labeled with state-of-the-art equipment in very high-resolution mass spectrometry and nanochromatography.
REQUIRED DEGREE : PhD
JOB DESCRIPTION
Multiomics and Big data integration can decipher the mode of action of drugs and possibly identify novel druggable targets as well as diagnostic or theragnostic-associated biomarkers. Alzheimer’s disease (AD) is characterized by complex neuropathological processes driven by amyloid deposition, neurofibrillary degeneration, astrogliosis, and neuroinflammation. Abeta peptides and Tau proteins, the respective components of amyloid deposits and neurofibrillary tangles, are believed to spread in a prion-like process from affected areas to interconnected brain regions. Drug development should ideally target the entire spectrum of AD pathophysiology rather than each process separately. We posit that protein aggregation and its neuroinflammatory and cognitive detrimental impacts can be targeted simultaneously by reinstating proper cellular/synaptic homeostasis without targeting specifically disease-associated aggregation-prone Abeta peptides and Tau proteins. Through phenotypic drug screening, our laboratories have developed five different families of small drugs with anti-AD efficacy. Drug candidate Ezeprogind (AZP2006), which represses Abeta1-x production and modulates autophagy, successfully completed a clinical phase IIa trial against progressive supranuclear palsy. Three further lead compounds mitigate in vivo both the amyloid and Tau pathologies and inflammation and cognitive deficits, hereinafter a drug-modifying paradigm. Based on solid preliminary results, our European Consortium team of experts in the field of AD, chemistry, prion-like propagation, neuroinflammation, big-data management and analysis, and biomarker development will pursue a highly innovative approach to identify molecular pathways that can be targeted for disease intervention. A combination of bioorthogonal chemistry-based strategies, chemoproteomics, and cell-based assays will allow the characterization of the cellular drug target(s). Characterization of the mode of action will be addressed by deep sequencing, pliceomics, single cell, spatial transcriptomics, Attac sequencing, miRNA epigenomics, and transcription factor footprinting. We envision deciphering the drug-target mechanism of action that mitigates the AD-related lesional processes, including the cellular processes related to the seeding and prion-like propagation, changes in gene expression associated with cognitive improvements, and the drug’s anti-neuroinflammatory properties. We will identify potential novel druggable target(s) and diagnostic or theragnostic biomarkers through Big data integrated analyses. This project will identify novel drug targets by characterizing modes of drug action toward aberrant protein deposition, neuroinflammatory processes, and cognitive benefits. Biomarkers, theragnostic markers, and potential druggable targets arising from multiomics big-data analyses might allow the repositioning of existing EMA-approved drugs to target AD.
The candidate will join a European consortium and will be more particularly involved in several tasks
- Establishment of libraries of Drugs and PhotoAffinity Labeling/Activity-based protein profiling (ABPP, also referred to as chemoproteomics) bifunctional probes
- Activity towards Tau Seeding, and Intercellular Extracellular Vesicles-Dependent Propagation of Tau Seeds, using Chemoproteomics for Target Identification and Target Interactome
- Target Validation and Mode of Action (MOA) towards Cognitive, Lesional, and Neuroinflammatory Processes
REQUIRED PROFILE :
PhD in Analytical Chemistry with a focus on mass spectrometry and proteomics
Prior practical experience in this field
Practical experience in high-resolution nanoLC/MS would be appreciated, as would a background in biochemistry/biology
Excellent communication in English and interpersonal skills
Ability to work independently and as part of a team
DURATION : 36 months
APPLICATION PROCESS :
Please send your CV, cover letter, transcripts, and references to joelle.vinh (at) espci.fr
ESPCI : www.smbp.espci.fr