Objective Chronic pain represents a major unmet medical need which has been linked to changes in voltage-gated sodium channels (VGSCs). These channels are transmembrane protein-complexes with a key-role in signal transmission in excitable cells, such as neurons, and allow the flux of Na+ ions through the cellular membrane in response to specific stimuli, thus controlling the generation and propagation of action potentials. Nine VGSC subtypes are known to be expressed in different cell types, and among them subtype Nav1.7 is of extreme interest since it is involved in nociceptive processing (pain-sensing) in the peripheral nervous system. Remarkably, patients suffering from congenital indifference to pain syndrome, which derives from loss-of-function mutations of the gene encoding for Nav1.7 have a dramatically reduced ability to perceive painful stimuli, but are otherwise perfectly healthy. Therefore, Nav1.7 has been recognized as an exciting target for pharmacological treatments of pain. However, detailed structural and functional information is lacking, and its attainment represents a fundamental step in the challenging task of finding Nav subtype-selective modulators. Thus, the main focus of my project is to study ligand-binding events with known modulators, thereby paving the way to the design of safe and selective inhibitors. I will develop, by solid phase peptide synthesis, a chemical probe specifically designed to isolate Nav1.7 using a tandem photoaffinity labeling-bioorthogonal conjugation approach. This probe will be applied in model cell lines expressing the channel, in order to study their binding interaction through mass spectrometry-based chemoproteomics. Once these chemical tools are established and validated in the model system, I will translate them to patient-derived cells, in order to study disease-relevant systems. Fields of science medical and health sciencesclinical medicineoncologyprostate cancernatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural sciencesbiological sciencesbiochemistrybiomoleculeslipidsmedical and health sciencesclinical medicineoncologybreast cancermedical and health sciencesclinical medicineoncologypancreatic cancer Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2014 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Net EU contribution € 183 454,80 Address SOUTH KENSINGTON CAMPUS EXHIBITION ROAD SW7 2AZ LONDON United Kingdom See on map Region London Inner London — West Westminster Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 183 454,80