Descripción del proyecto
Hacer avanzar los ensayos para el descubrimiento de fármacos
El descubrimiento de dianas terapéuticas constituye un paso clave en el proceso de descubrimiento de fármacos, en el que se evalúan sustancias químicas de diversos procesos biológicos mediante cribado de alto rendimiento (HTS, por sus siglas en inglés). El proyecto financiado con fondos europeos HTS MALDI-TOF MDD tiene por objeto incorporar la espectrometría de masas de desorción/ionización mediante láser asistida por matriz y asociada a un analizador de tiempo de vuelo (MALDI-TOF) en los ensayos de metabolómica celular. El plan es investigar en qué medida afectan los fármacos a las distintas vías metabólicas y trazar de forma simultánea el perfil metabólico de la célula. A partir de un modelo celular de fibrosis pulmonar, los investigadores evaluarán si algún metabolito en particular puede actuar como biomarcador para el diagnóstico de la enfermedad y como valor de lectura en ensayos para el descubrimiento de fármacos.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
NE1 7RU Newcastle Upon Tyne
Reino Unido