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BCM-UPS SIGNED

Dissecting the role of the ubiquitin proteasome system in the pathogenesis and therapy of B-cell malignancies

Total Cost €

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EC-Contrib. €

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Partnership

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 BCM-UPS project word cloud

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

genome    dna    candidate    tumour    genomic    preclinical    genetic    drugs    damage    cell    ubiquitin    prognosis    substrates    lymphoma    inhibitors    dub    pathogenesis    suppressors    machinery    malignancies    mouse    fundamental    distinguished    discovered    multistep    suggests    ligases    mass    pathophysiology    disease    critically    screens    mm    cellular    identities    efficacy    treatment    previously    reaching    orphan    ubiquitylation    roles    appreciated    dubs    ligase    ring    validate    evolution    family    proteasome    relevance    deubiquitylating    interdisciplinary    cohorts    counterparts    maintaining    crl    unravel    foundation    mantle    spectrometry    therapeutic    myeloma    cullin    modalities    imunomodulatory    integrity    crbn    multiple    oncogenes    entities    fbxo25    mcl    ups    respectively    patient    remained    fbxo3    events    global    aberrant    biomarkers    hypothesis    levels    decipher    candidates    instability    strategy    imids    usp24    deregulated    poor    incurable    models    serve    mostly    crls    elusive    enzymes   

Project "BCM-UPS" data sheet

The following table provides information about the project.

Coordinator
KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN 

Organization address
address: ISMANINGER STRASSE 22
city: MUENCHEN
postcode: 81675
website: http://www.med.tu.muenchen.de

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

 Coordinator Country Germany [DE]
 Total cost 1˙973˙255 €
 EC max contribution 1˙973˙255 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2015-CoG
 Funding Scheme ERC-COG
 Starting year 2016
 Duration (year-month-day) from 2016-09-01   to  2021-08-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN DE (MUENCHEN) coordinator 1˙973˙255.00

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 Project objective

B-cell malignancies are characterized by high levels of genomic instability, which critically contribute to their pathogenesis and evolution. Recently, the fundamental role of the ubiquitin proteasome system (UPS) in maintaining genome integrity has been appreciated. Two major new therapeutic modalities in B-cell malignancies, proteasome inhibitors and imunomodulatory drugs (IMiDs), target the UPS and demonstrate particular efficacy in multiple myeloma (MM) and mantle cell lymphoma (MCL), two incurable entities with poor prognosis. This suggests the presence of aberrant ubiquitylation events, whose identities have however remained mostly elusive. Our recent studies identify fundamental roles of orphan ubiquitin ligases of the Cullin Ring ligase family (CRLs) and their counterparts, the deubiquitylating enzymes (DUBs) in the cellular DNA damage response machinery, and characterize these candidates as novel oncogenes or tumour suppressors in MM and MCL. These findings provide the foundation for our hypothesis that deregulated ubiquitylation events involving CRLs and DUBs have a far reaching impact on the pathogenesis of B-cell malignancies and can serve as new therapeutic targets and biomarkers. We therefore propose a multistep strategy in which we will (1) characterize previously orphan CRLs and DUBs, which we have distinguished as candidate oncogenes and tumour suppressors in MM (FBXO3, USP24), MCL (FBXO25), or MM and MCL (CRBN), respectively; (2) decipher the global role of CRLs and DUBs in MM and MCL using defined genetic screens; (3) identify relevant substrates of CRLs/DUBs discovered in (2) using mass spectrometry; and (4) validate CRL/DUB candidates in preclinical mouse models and defined patient cohorts as to their disease relevance. We expect that our interdisciplinary approach will unravel the overall role of the UPS in the pathophysiology, evolution and treatment of B-cell malignancies.

 Publications

year authors and title journal last update
List of publications.
2018 Catharina Wenk, Anne-Kathrin Garz, Sonja Grath, Christina Huberle, Denis Witham, Marie Weickert, Roberto Malinverni, Julia Niggemeyer, Michèle Kyncl, Judith Hecker, Charlotta Pagel, Christopher B. Mulholland, Catharina Müller-Thomas, Heinrich Leonhardt, Florian Bassermann, Robert A. J. Oostendorp, Klaus H. Metzeler, Marcus Buschbeck, Katharina S. Götze
Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis
published pages: 3447-3461, ISSN: 2473-9529, DOI: 10.1182/bloodadvances.2018022053
Blood Advances 2/23 2019-06-06

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