Objective Protein kinases play a critical role in a number of cellular processes, including cell proliferation, differentiation and apoptosis. Recently, the aberrant regulation of lymphocyte-specific protein tyrosine kinases (LCK) has been associated with the over activation of microglia cells (important immune effector cells that reside in the central nervous system, CNS) and in turn, the development of Alzheimer’s disease (AD). Unfortunately, the detail of LCK's dynamic function and the importance of quantitative, spatial and time-dependent parameters regarding microglia activation is poorly understood. As such, the ability to manipulate LCK activity using light would result in temporal control of enzymatic activity, thus serving as a valuable approach to probe the function of LCK in microglia cells and in turn, further our understanding of AD and related neurodegenerative disorders. While such studies cannot be performed using conventional LCK inhibitors, this project aims to control the enzymatic activity of LCK by the development of a stimuli-responsive release-and-report system, through the introduction of a photolabile 'caging' moiety onto a fluorescent kinase inhibitor. The caging group will also consist of an appropriate ‘quencher’, quenching the innate fluorescence properties of the inhibitor through energy transfer (FRET). Exposure to light (> 320 nm) will result in decaging of the prodrug to give the active form, while simultaneously switching ‘on’ the fluorescence — reporting back to the user that the compound has been activated. To demonstrate the potential of the release-and-report kinase inhibitor as a tool to probe LCK function in microglia cells, confocal microscopy will be employed to visualise the site of microglia activation and the time frame during CNS development in zebrafish model systems. Fields of science natural sciencesbiological sciencesneurobiologymedical and health sciencesbasic medicinepharmacology and pharmacydrug discoverymedical and health sciencesbasic medicineneurologydementiaalzheimernatural sciencesphysical sciencesopticsmicroscopyconfocal microscopynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes 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-2016 - Individual Fellowships Call for proposal H2020-MSCA-IF-2016 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator GOETEBORGS UNIVERSITET Net EU contribution € 173 857,20 Address VASAPARKEN 405 30 Goeteborg Sweden See on map Region Södra Sverige Västsverige Västra Götalands län 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 € 173 857,20
