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MRC DiMeN Doctoral Training Partnership: Developing microfluidic devices for cellular modelling of inherited eye diseases


Project Description

Inherited retinal dystrophies are a leading cause of blindness and visual loss. Over 20,000 individuals in the UK are registered blind or partially sighted because of these conditions, caused by mutations in over 260 genes. However, many genetic variants do not have an ascribed functional significance. Our current inability to interpret the functional consequences of “variants of uncertain significance” limits the value of genetic information for many patients. Understanding the impact of “variants of uncertain significance” allows accurate counselling of patients, improves our knowledge of disease pathogenesis and catalyses the development of novel treatments. Cellular modelling of variants by using microfluidic devices has the potential to hugely increase throughput and capacity of functional assays, but it is an approach that is currently under-studied and under-developed for retinal cells.

You will use well-established protocols to differentiate induced pluripotent stem cells (iPSCs) into retinal cell types. Variants identified from patients will be genome-edited into iPSCs by using standard CRISPR-Cas9 knock-in methods. You will then differentiate physiological tissue systems on novel “organ-on-a-chip” microfluidic devices, and use these devices to address the current limitations of genetic variant interpretation. The overall aim of the project is to develop novel and improved methods of in vitro cellular modelling. “Organ-on-a-chip” devices are a clear opportunity to improve throughput and reproducibility through minimizing culture volumes and reducing cell manipulation. This will enable matched sets of functional assays, with a particular focus on using these devices for pre-clinical testing of new therapeutic strategies such as allele-specific knockdown and antisense oligonucleotide therapy.

The project provides an exciting opportunity to start a research career by combining the new field of stem cell biology with biomedical engineering. You must demonstrate a strong background in biochemistry or molecular cell biology with a first degree in a relevant biomedical subject, and have the ability and ambition to develop a successful multidisciplinary research project. As part of this project, you will learn important methodologies in stem cell differentiation, microfluidic device design and manufacture, microscopy and functional cell biological assays.

Supervisors web pages:
https://medicinehealth.leeds.ac.uk/medicine/staff/478/professor-colin-a-johnson
https://www.bioelectronics.leeds.ac.uk
Twitter: @johnsoncilialab

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!

References

Buskin A, Zhu L, Chichagova V, Basu B, Mozaffari-Jovin S, …33 others… Grellscheid S-N, Johnson CA, Lako M (2018). Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nat Commun 9:4234 doi: 10.1038/s41467-018-06448-y https://rdcu.be/85uN

Smith AJ, O'Rorke RD, Kale A, Rimsa R, Tomlinson MJ, Kirkham J, Davies AG, Wälti C, Wood CD (2017). Rapid cell separation with minimal manipulation for autologous cell therapies. Sci Rep 7:41872 doi: 10.1038/srep41872

Rimsa R, Smith AJ, Wälti C, Wood CD (2017). A planar surface acoustic wave micropump for closed-loop microfluidics. Appl Phys Lett 111:234102 doi.org/10.1063/1.5007701

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