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TargetDUBs SIGNED

Targeting ubiquitin processing in cancer and fibrosis: novel probes for the Ubiquitin Carboxy-Terminal Hydrolases

Total Cost €

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EC-Contrib. €

0

Partnership

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 TargetDUBs project word cloud

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

small    ub    tissues    carboxy    therapeutics    degrade    enzymes    tool    irreversible    cancers    hundreds    proteins    explore    experiments    models    endogenous    realize    quantitatively    simultaneously    substrates    ubiquitin    dysregulation    assisting    deubiquitination    protein    pathological    biology    emerged    proteome    lung    uchl1    discovery    prevent    driving    synthesize    itself    anticipate    quantification    proteasome    profiling    alzheimer    ligase    selectively    cellular    cells    shown    mechanism    ovarian    modification    types    therapeutic    deubiquitinases    actual    starting    parkinson    uch    disease    terminal    proteomics    liver    e3    drug    protacs    l1    fibrosis    fundamental    almost    dubs    vitro    unmet    effect    cancer    molecules    inhibitors    colorectal    point    diseases    headed    direct    healthy    breast    poorly    removal    regulation    identification    hydrolase    prostate    family    selective    probes    abundant    neurodegenerative    brain    regulated    degradation    functions    overcome    paradigm    limitations    vivo   

Project "TargetDUBs" data sheet

The following table provides information about the project.

Coordinator
IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE 

Organization address
address: SOUTH KENSINGTON CAMPUS EXHIBITION ROAD
city: LONDON
postcode: SW7 2AZ
website: http://www.imperial.ac.uk/

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 United Kingdom [UK]
 Total cost 224˙933 €
 EC max contribution 224˙933 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2018
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2019
 Duration (year-month-day) from 2019-08-01   to  2021-07-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE UK (LONDON) coordinator 224˙933.00

Map

 Project objective

Modification of proteins with ubiquitin (Ub), itself a small protein, is a fundamental mechanism involved in regulation of almost all cellular functions. There are hundreds of enzymes involved in the addition or removal of Ub, and this system has emerged as an important drug target in many diseases. Ubiquitin Carboxy-Terminal Hydrolase L1 (UCHL1) is a member of the UCH family of deubiquitinases (DUBs), and is the most abundant protein in the brain. UCHL1 dysregulation has been shown to be associated with neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, various types of cancers (colorectal, breast, prostate, ovarian, and lung cancers), and liver fibrosis. However, its actual functions, endogenous substrates, and how its activity is regulated in vivo, both in pathological and healthy tissues, remain poorly understood. To overcome these limitations and to realize the unmet therapeutic opportunities, I will develop and synthesize activity-based probes to selectively target UCHL1, and will apply them to the identification and quantification of UCH enzymes in several cancer cells using activity-based protein profiling. This will provide a unique tool to explore a wide range of DUBs and UCH biology in cells, as well as a starting point to develop selective inhibitors and potential therapeutics. Simultaneously, I will develop and synthesize irreversible PROTACs to selectively degrade UCHL1 and will apply them to quantitatively assess their effect on UCH enzymes in several in vitro cancer and fibrosis models using proteome-wide proteomics experiments. PROTACs are two-headed molecules capable to direct E3 ubiquitin ligase activity towards the target protein, driving its degradation by proteasome. I anticipate that novel PROTACs based on inhibitors that target UCHL1 would provide a unique tool to degrade UCHL1 and prevent deubiquitination, assisting discovery of novel UCHL1 substrates and providing a new paradigm for targeting UCHL1 in disease.

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The information about "TARGETDUBS" are provided by the European Opendata Portal: CORDIS opendata.

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