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PCAGED-KI

Photocaged Kinase Inhibitors as Molecular Tools for Investigating Neurodegenerative Diseases

Total Cost €

0

EC-Contrib. €

0

Partnership

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 PCAGED-KI project word cloud

Explore the words cloud of the PCAGED-KI project. It provides you a very rough idea of what is the project "PCAGED-KI" about.

prodrug    alzheimer    release    report    spatial    tool    protein    central    dependent    frame    regulation    inhibitor    unfortunately    differentiation    manipulate    give    proliferation    apoptosis    quantitative    fluorescent    critical    gt    form    nervous    energy    conventional    model    dynamic    quencher    employed    activation    appropriate    function    regarding    responsive    kinase    lck    group    transfer    activated    effector    inhibitors    320    reporting    disease    immune    reside    microscopy    serving    compound    introduction    switching    time    nm    cellular    simultaneously    turn    fluorescence    photolabile    caging    exposure    ad    quenching    valuable    poorly    neurodegenerative    aberrant    innate    onto    microglia    fret    light    cells    consist    decaging    visualise    enzymatic    probe    moiety    disorders    play    temporal    kinases    active    tyrosine    stimuli    cell    back    site    cns    lymphocyte    performed    zebrafish    confocal   

Project "PCAGED-KI" data sheet

The following table provides information about the project.

Coordinator
GOETEBORGS UNIVERSITET 

Organization address
address: VASAPARKEN
city: GOETEBORG
postcode: 405 30
website: www.gu.se

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Sweden [SE]
 Project website http://grotlilab.net/research/photopharmacology/kinase-inhibitors/
 Total cost 173˙857 €
 EC max contribution 173˙857 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2016
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2017
 Duration (year-month-day) from 2017-10-01   to  2019-09-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    GOETEBORGS UNIVERSITET SE (GOETEBORG) coordinator 173˙857.00

Map

 Project 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.

 Publications

year authors and title journal last update
List of publications.
2019 Cassandra L. Fleming, Morten Grøtli, Joakim Andréasson
On‐Command Regulation of Kinase Activity using Photonic Stimuli
published pages: 318-326, ISSN: 2367-0932, DOI: 10.1002/cptc.201800253
ChemPhotoChem 3/6 2020-02-12
2018 Cassandra L. Fleming, Shiming Li, Morten Grøtli, Joakim Andréasson
Shining New Light on the Spiropyran Photoswitch: A Photocage Decides between cis – trans or Spiro-Merocyanine Isomerization
published pages: 14069-14072, ISSN: 0002-7863, DOI: 10.1021/jacs.8b09523
Journal of the American Chemical Society 140/43 2020-02-12
2019 Cassandra L. Fleming, Patrick A. Sandoz, Tord Inghardt, Björn Önfelt, Morten Grøtli, Joakim Andréasson
A Fluorescent Kinase Inhibitor that Exhibits Diagnostic Changes in Emission upon Binding
published pages: 15000-15004, ISSN: 1433-7851, DOI: 10.1002/anie.201909536
Angewandte Chemie International Edition 58/42 2020-02-12

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