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MRC DiMeN Doctoral Training Partnership: DUB-ing chronic inflammation: a drug repurposing approach to target deubiquitinases in inflammatory disease


Project Description

Background:

Inflammation is an essential defence mechanism adapted by our bodies to eliminate damaged cells, irritants and pathogens. However, persisting inflammation that fails to resolve promotes or contributes to a number of chronic diseases including cancer, rheumatoid arthritis and musculoskeletal diseases. Chronic or persistent inflammation in tissues results in pain, tissue damage and loss of function. The cellular and molecular mechanisms of this tissue destruction are poorly understood. Our group focuses on identifying therapeutic targets for chronic inflammation induced by mechanical tissue injury. Identifying the cellular mechanisms involved in injury responses is crucial for understanding disease mechanisms and for designing specifically tailored therapeutic regimens for chronic inflammatory diseases.

We showed that mechanical injury to connective tissues activates within seconds intracellular signalling pathways that are characteristic of the inflammatory response. Recent evidence from our studies showed a great significance of the ubiquitin system as an upstream regulator of these cellular events. The ubiquitin system comprises a group of enzymes that facilitate post-translational modifications of proteins by ubiquitination which is emerging as a critical regulator of inflammatory signalling pathways. Ubiquitination is a reversible and dynamic reaction which is tightly controlled by the opposing actions of ubiquitin ligases and deubiquitinating enzymes (DUBs). DUBs are important players in the ubiquitin system. They are cysteine- and metallo-proteases that work by reversing and editing ubiquitination in a specific manner with several roles in ubiquitin homeostasis and negative regulation of ubiquitin signalling. DUB deregulation contributes to various disorders and age-related tissue degeneration.

In this project, the student will delineate the role of a group of candidate deubiquitinases (DUBs) in inflammatory cellular responses to mechanical tissue injury in vivo.


Specific aims of the project:

- To identify specific inhibitors for targeting candidate DUBs in injury-induced inflammation using a custom library of FDA approved compounds.
- To modulate candidate DUBs activity in vivo using loss/gain of function Zebrafish models
- To determine the functional role of candidate DUBs in in vivo models of tissue injury and inflammation


Novelty and timeliness:

Targeting DUBs is emerging as a significant new drug discovery opportunity targeting chronic diseases such as cancer and inflammatory diseases.


Experimental Approach:

The student will become expert in using the zebrafish in vivo model system, in which high-throughput screening is possible and will gain experimental experience of in vivo model systems and cell biology approaches, gene manipulation and editing techniques, biochemical analysis, mathematical modelling using machine learning and advanced data analysis techniques. Training provided will enhance the candidate employee skill-base for the medical, pharmaceutical and biotech industries and increase their competitiveness and employability chances.


Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs.
Includes:
- Stipend at national UKRI standard rate
- Tuition fees
- Research training and support grant (RTSG)
- Travel allowance

Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

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