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MRC DiMeN Doctoral Training Partnership: Personalised medicine in Joubert syndrome: patient-specific human urine-derived epithelial cells as a disease model and platform for therapeutic development

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  • Full or part time
    Prof J Sayer
    Dr C Miles
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

“Ciliopathies” account for 10% of the 40,000 UK patients requiring dialysis/transplantation. These disorders cause cystic kidney disease, retinal degeneration and brain abnormalities, as typified by Joubert syndrome (JS) but widespread genotype-phenotype heterogeneity poses a challenge for dissecting disease pathobiology. There are currently no disease-modifying treatments for these conditions and the development of treatments will require patient-specific, personalised approaches.

The supervisors ( and have developed a “pipeline” from gene discovery [eg, Nat Genet. 2006 38(6):674; Am J Hum Genet. 2018 103(4):612], through creation of mouse models [eg, Proc Natl Acad Sci USA. 2014 111(27):9893]
for identification of therapeutic targets, and back to the patient for testing and validation of potential treatments on kidney cells directly isolated from patients [eg, Hum Mol Genet. 2017 26(23):4657 & Proc Natl Acad Sci 2018]], known as human Urine-derived-Renal-Epithelial-Cells (hURECs)n

Whilst the supervisors lead the field in research involving hURECs, these cells remain the least understood part of this pipeline and further detailed understanding and development of this platform will be essential for translating our findings to the clinic. Currently studies involving hURECs are limited to those patients within a few hours of the laboratory and there is an urgent need to overcome this limitation, eg, we have patients worldwide (from USA to the Middle East) but at present must send our researchers to where the patients are. Therefore, in parallel, this project will be carried out in collaboration with Atelerix ( pioneers in the storage and transport of specialised human cells.

The project will involve detailed phenotypic characterisation of hURECs from a panel of JS patients compared with hURECs from healthy volunteers and hURECs that have been engineered (siRNA and/or CRISPR/Cas9) to model specific
aspects of disease. In addition to standard immunohistochemistry, a key enabling technology for this project is the Genomics Core Facility underpinned by recent >£1M investments from Newcastle University (
) that will allow us to perform “single cell RNAseq” on hURECs to characterise these cells in unprecedented detail. These data will be overlayed on normal kidney datasets to precisely define the cellular composition of hUREC cultures and subsequently, disease
mechanisms will be identified by comparison with data from patient-specific mouse models (ie, mice engineered to carry the identical amino acid change as the patient).

This PhD will provide a comprehensive training in state-of-the-art human disease genetics coupled with an industrial perspective on the development of essential technologies, delivered by a multidisciplinary team at the forefront
of ciliopathy research.

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:
Further information on the programme can be found on our website:

Funding Notes

iCASE Award: Industrial partnership project
Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.
Studentships commence: 1st October 2019.

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:
Good luck!


1: Ramsbottom SA, Molinari E, Srivastava S, Silberman F, Henry C, Alkanderi S, Devlin LA, White K, Steel DH, Saunier S, Miles CG, Sayer JA. Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model. Proc Natl Acad Sci U S A. 2018 Nov 16. pii: 201809432. doi: 10.1073/pnas.1809432115. [Epub ahead of print] PubMed PMID: 30446612.

2: Alkanderi S, Molinari E, Shaheen R, Elmaghloob Y, Stephen LA, Sammut V, Ramsbottom SA, Srivastava S, Cairns G, Edwards N, Rice SJ, Ewida N, Alhashem A, White K, Miles CG, Steel DH, Alkuraya FS, Ismail S, Sayer JA. ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition. Am J Hum Genet. 2018 Oct 4;103(4):612-620. doi: 10.1016/j.ajhg.2018.08.015. Epub 2018 Sep 27. PubMed PMID: 30269812; PubMed Central PMCID: PMC6174286.

3: Molinari E, Decker E, Mabillard H, Tellez J, Srivastava S, Raman S, Wood K, Kempf C, Alkanderi S, Ramsbottom SA, Miles CG, Johnson CA, Hildebrandt F, Bergmann C, Sayer JA. Human urine-derived renal epithelial cells provide insights into kidney-specific alternate splicing variants. Eur J Hum Genet. 2018 Dec;26(12):1791-1796. doi: 10.1038/s41431-018-0212-5. Epub 2018 Jul 12. PubMed
PMID: 30002499; PubMed Central PMCID: PMC6244279.

How good is research at Newcastle University in Clinical Medicine?

FTE Category A staff submitted: 147.13

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