Stem cell modelling of genomic rearrangements that cause retinal degeneration

Institute of Ophthalmology 3-Year PhD Studentship

UCL Department / Division: UCL Institute of Ophthalmology, Faculty of Brain Sciences

Duration of Studentship: 3 years, commencing October 1^st 2024

PhD Title: Stem cell modelling of genomic rearrangements that cause retinal degeneration

Supervisor(s): Professor Alison Hardcastle and Professor Mike Cheetham

We are delighted to offer a full–time, three year PhD studentship to develop stem cell derived retinal organoid models of dominant retinitis pigmentosa (RP) caused by structural variants (SVs).   

We recently discovered that SVs on chromosome 17 are a major cause of previously unsolved autosomal dominant RP (de Bruijn et al 2020). Here, we will use stem cell derived patient retinal organoids to investigate the molecular mechanisms that drive RP17 retinal dystrophy. This studentship is part of a multi-disciplinary research consortium funded by the Foundation Fighting Blindness (USA), a collaboration with international teams. We will focus on using retinal organoids to understand disease and develop potential therapies. The student will characterise how the SVs alter gene expression, lipid homeostasis and cell morphology. They will also use a range of methods to modify gene expression (CRISPR gene editing, viral gene augmentation, knock-down) in order to experimentally interrogate disease mechanisms and test new therapeutics. 

Applicants should hold, or expect to receive, a minimum upper-second degree or equivalent in an associated subject such as biology, biomedical science, neuroscience or life science with a strong background in cell biology and genetics. A Master’s degree and/or previous relevant lab-based research experience is highly desirable.

References

de Bruijn SE, Fiorentino A, Ottaviani D, Fanucchi S, Melo US, Corral-Serrano JC, Mulders T, Georgiou M, Rivolta C, Pontikos N, Arno G, Roberts L, Greenberg J, Albert S, Gilissen C, Aben M, Rebello G, Mead S, Raymond FL, Corominas J, Smith CEL, Kremer H, Downes S, Black GC, Webster AR, Inglehearn CF, van den Born LI, Koenekoop RK, Michaelides M, Ramesar RS, Hoyng CB, Mundlos S, Mhlanga MM, Cremers FPM, Cheetham ME, Roosing S, Hardcastle AJ. Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa. Am J Hum Genet. 2020 Nov 5;107(5):802-814. doi: 10.1016/j.ajhg.2020.09.002. PMID: 33022222.

Duties and Responsibilities

The successful candidate is expected to:

• Differentiate patient derived stem cells to retinal organoids and characterise them at the molecular and cellular level (morphology, transcriptomics, proteomics, lipidomics)

• Use gene editing of stem cells to produce modifications to structural variants.  

• Modify gene expression using viral mediated gene augmentation or gene directed knockdown

• Work in collaboration with other researchers at UCL and with our international collaborators

• Prepare progress reports

• Prepare presentations

• Travel for collaboration and other meetings or conferences

• Prepare manuscripts for submission to international peer-reviewed journals

• Contribute to the overall activities of the research team and department and be aware of UCL policies

Person Specification

• A relevant undergraduate degree (2.1 or above; or the equivalent EU/overseas degree) and/or an MSc in a biomedical field (e.g. Neuroscience, Cell biology, or Genetics)

• Demonstrable interest in working with stem cell models and translational medicine

• Experience of tissue culture (in particular stem cell culture and differentiation), immunocytochemistry, gene editing, western blotting, transcriptomics or lipidomics is highly desirable

• Excellent technical skills, particularly in project planning

• Experience with statistical methods and software packages

• High proficiency in written and spoken English is required

• A strong work ethic with an ability to think creatively and work both individually and within a team

• Excellent communication skills: verbal and written skills that enable positive working dynamics within lab teams and with external organisations and stakeholders.

Commencement

The successful candidate is expected to start 1 October 2024. Some flexibility with the start date may be possible and can be discussed further at interview.

Funding Notes

This studentship is funded for three years by Foundation Fighting Blindness (USA) and is inclusive of UK home rate tuition fees, laboratory costs and an annual stipend starting at GBP £22,000. International students: please see the details in the Eligibility item below.

 

Eligibility

The full studentship (tuition fees and salary stipend) is eligible to all candidates classed as home tuition fee status. In addition, some EU nationals may also be eligible, depending on their settlement status.

Applicants classed by UCL as overseas for tuition fee status will incur the international tuition fee rates. We welcome applications from such candidates on condition they would be able to self-pay the difference between the home and international fees (per here: https://www.ucl.ac.uk/students/fees-and-funding/pay-your-fees/fee-schedules/2024-2025/postgraduate-research-fees-2024-2025 the difference for AY2024/25 the difference stands at £28,365 for year AY2024/25 and is subject to moderate increases in future years).

Enquiries

Informal enquiries relating to the project and/or opportunity should be made to Prof. Alison Hardcastle at a.hardcastle@ucl.ac.uk.

Queries of an administrative nature relating to the application process and general questions can be sent to the Research Degrees Manager at ioo.pgr@ucl.ac.uk.

How to apply

Please prepare a single PDF document in the following order:

·      A covering letter outlining motivation, interest, and suitability for this project (NB: please include the PhD title and reference AHMCJLY24 in your cover letter);

·      CV / resume

·      Contact details for two academic referees

Attach to an email with the reference AHMCJLY24 in the subject line and send to the Research Degrees Manager at ioo.pgr@ucl.ac.uk by the deadline stated below. We ask that applicants follow these instructions carefully since deviation may invalidate your application. Any details specified in the body of email messages will not form part of the application.

Application deadline: 23:59 British Summer Time (BST) Sunday 4 August 2024.

Proposed interview date: Week beginning 12 August 2024. Shortlisted candidates will be contacted directly with further details of interview times.