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Modulation of healthy ageing by STUB1/CHIP

College of Medicine and Veterinary Medicine

About the Project

Deanery of Biomedical Sciences

Project Description for Advert (max 500 words). This will be the text that is advertised to prospective students:

The proposed interdisciplinary project will exploit the power and speed of the C. elegans model to assess the role of CHIP in healthy ageing and nervous system function in the context of a living organism.

CHIP is an abundantly expressed, multifunctional protein with both co-chaperone and ubiquitin ligase activity. Compelling evidence implicates CHIP in healthy ageing. Mutations in CHIP cause pathological conditions in humans, such as ataxias, and loss or misfunction of CHIP in mice leads to premature ageing, plus motor and cognitive decline1.

CHIP has been traditionally studied for its role within the chaperone network where it regulates folding and degradation of misfolded proteins in stress conditions. Non-canonical roles for CHIP were recently revealed under unstressed physiological conditions, in maintaining cellular and organismal health, through the regulation of native folded proteins. In C. elegans and flies CHIP was shown to ubiquitinate the insulin receptor DAF-2, regulating insulin signalling and lifespan2. The Ball laboratory and others uncovered non-canonical, chaperone-independent functions of CHIP in regulating immune system components such as IRF33, and a cohort of native proteins involved in membrane integrity, vesicle formation and actin cytoskeleton maintenance (in preparation, Ball). Uncovering native CHIP substrates and understanding how they are regulated by CHIP will provide novel insights into the role of this ligase in ageing and neuroprotection.

The specific objectives of the project are:
i) Generate a multi-omics dataset using RNA-Seq and label free mass spectrometry with C. elegans wild-type and CHIP loss-of-function strains, under stress and normal conditions. The C. elegans dataset will be cross-referenced with previously obtained datasets from human stem- and cancer-cell model systems.
ii) Carry out functional validation of potential candidate substrates for CHIP through biochemical, genetic, and behavioural approaches using C. elegans. Priority will be given to cross-species substrates, i.e. proteins commonly identified in datasets obtained from C. elegans and human cultured neurons. Candidate CHIP substrates previously identified in cultured neurons have C. elegans orthologs with known morphological and behavioural phenotypes that can be quantified using established assays.
iii) Assess the functional significance of known CHIP mutations and their effect on target proteins and ageing phenotypes. This will be achieved by modifying the genetic locus for CHIP via CRISPR genome editing.

Central to the PhD project is training in Bioinformatics for proteomics and RNA-Seq data analysis, state-of-the-art molecular genetics, biochemistry and behavioural analysis methods. The project focusing on C. elegans studies, will synergise with an existing EASTBIO collaboration of the Doitsidou and Ball laboratories, which has focused on CHIP studies in human cells. This new collaboration will further support cross-disciplinary training of both students.

[1] Shi CH et al. Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. PLoS Genet. 2018;14(9):e1007664
[2] Tawo R et al. The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover. Cell. 2017;169(3):470-482.e13
[3] Narayan V et al. Docking-dependent ubiquitination of the interferon regulatory factor-1 tumor suppressor protein by the ubiquitin ligase CHIP. J Biol Chem. 2011;286(1):607-619

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership. This opportunity is open to UK and international students and provides funding to cover stipend and UK level tuition fees. The UoE covers the difference between home and international fees. There is a cap on the number of international students the DTP can recruit so it is important to know in which fees status category applicants fall under when applying.

Refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.

Funding Notes

Application Procedure
Download application and reference forms from View Website

Completed application form along with your supporting documents should be sent to our PGR student team at by 6th January 2021.

References: Please send the reference request form to two referees. Completed references for this project should also be returned to by the closing date: 6th January 2021.

It is your responsibility to ensure that references are provided by the specified deadline.

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