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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. €

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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.

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

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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