Project description
A silver bullet for numerous diseases could target the most ubiquitous protein in the brain
Ubiquitin is a small, highly conserved protein that is found in all eukaryotic cells. It plays a central role in numerous cell processes including cell-cycle regulation, DNA repair, cell growth, signalling and immunity. It plays a fundamental role in health and sickness. The most abundant protein in the brain, more ubiquitous than ubiquitin, is a deubiquitinating enzyme (DUB) associated with numerous and varied diseases. Its mechanism of action and regulation are not well-characterised. The TargetDUBs project is developing novel probes for specific DUBs and techniques to selectively degrade the most abundant one. Enhanced understanding could point the way to targeted therapies for diseases affecting millions of people worldwide.
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- medical and health sciences basic medicine neurology dementia alzheimer
- medical and health sciences clinical medicine oncology lung cancer
- medical and health sciences basic medicine neurology parkinson
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF-EF-ST - Standard EF
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2018
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
SW7 2AZ London
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.