Description du projet
Faire progresser les tests sur la découverte de médicaments
La découverte de cibles thérapeutiques constitue une étape clé dans le processus de découverte de médicaments, où des substances chimiques sont évaluées par criblage à haut débit (HTS) dans différents processus biologiques. Le champ d’application du projet HTS MALDI‑TOF MDD, financé par l’UE, porte sur l’intégration de la spectrométrie de masse à temps de vol et de désorption‑ionisation laser assistée par matrice (MALDI‑TOF) dans des essais sur la métabolomique cellulaire. L’objectif consiste à étudier la manière dont les médicaments affectent différentes voies métaboliques et à cartographier simultanément le profil métabolique de la cellule. En utilisant un modèle cellulaire de la fibrose pulmonaire, les chercheurs s’attacheront à savoir si des métabolites particuliers peuvent servir de biomarqueurs pour le diagnostic des maladies, ainsi que de lecture dans les essais sur la découverte de médicaments.
Objectif
Discovery for drug targets is a key step within the process of drug development, and is the corner stone in the pharmaceutical industry. This is mostly achieved by high-throughput screening (HTS) approaches in which a large number of chemical substances are assayed for a specific effect or activity in diverse areas of biology. Mass spectrometry (MS) has become a widely adopted tool in this field as it offers the possibility to simultaneously track molecules in a label-free manner, provides excellent signal to noise, reproducibility, assay precision, and a significantly reduced reagent cost when compared to fluorescence-based assays. Matrix-assisted laser/desorption ionisation time of flight (MALDI-TOF) is the most validated surface ionisation method for HTS approaches, but reported applications of this technology have been limited to in vitro assays with simple readouts and to peptide/protein-centric activity assays. To date, comprehensive and unbiased metabolomics based HTS approaches for cellular assays with MALDI-TOF have not been explored. The objective of this fellowship is to set up a MALDI-TOF based cellular assay for HTS metabolomics drug discovery in order to identify a set of metabolites to screen which will enable us to unbiasly and comprehensibly measure, in a HT manner, how drugs affect different metabolic pathways while simultaneously mapping the metabolic profile of the cell. First, I will develop a robust protocol for the detection, identification, and quantification of ~50 small metabolites for cellular assays. Then, I will apply this protocol to track metabolites in a pulmonary fibrosis cellular model, as well as in fibrotic lung tissue sections using MS imaging. The goal is to compare a disease model with the control to see how drugs are affecting these metabolites, and to see if identified biomarkers can be used to identify disease in tissue samples. As a final validation step, I will implement this platform in Boehringer Ingelheim in Germany.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
NE1 7RU Newcastle Upon Tyne
Royaume-Uni