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Generation of transplant tissue following correction of patient stem cells by genomic engineering


Project Description

A number of retinal degenerations result from mutations in genes expressed in the retinal pigment epithelium (RPE) which lies under the photoreceptors. An alternative approach to gene therapy is to replace the diseased tissue; an approach that has been pioneered by Japanese researchers who transplanted allogenic RPE into patients with age related macular degeneration. RPE derived from embryonic stem cells is also being investigated for transplant in patients with age-related macular degeneration.

In this project we generate induced pluripotent stem cells (iPSCs) from the blood of patients with retinal degenerations caused by mutations in bestrophin-1, a chloride channel in the RPE. We will then use CRISPR-Cas9 genome engineering to correct the pathogenic mutation in the iPSCs before using directed differentiation to generate RPE.

The student will learn all aspects of cell culture, reprograming of terminally differentiated to iPSC, design and application of CRISPR-Cas9 genome engineering, and cell differentiation and characterisation.

Dr Manson has had a long time interest in retinal degenerations, particularly around bestrophin-1, and has wide experience in model systems and molecular biology. Dr Taylor has expertise in the molecular diagnosis of genetic eye disease and has experience of generating iPSC-RPE from blood cells. Dr Adamson is the manager of the University’s Transgenic Unit and uses CRISPR-Cas9 on a daily basis in a wide range of experimental systems and animal models.

Entry Requirements:

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with previous laboratory experience, particularly in cell culture and molecular biology, are encouraged to apply. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y, Terada M, Nomiya Y, Tanishima S, Nakamura M, Kamao H, Sugita S, Onishi A, Ito T, Fujita K, Kawamata S, Go MJ, Shinohara C, Hata KI, Sawada M, Yamamoto M, Ohta S, Ohara Y, Yoshida K, Kuwahara J, Kitano Y, Amano N, Umekage M, Kitaoka F, Tanaka A, Okada C, Takasu N, Ogawa S, Yamanaka S, Takahashi M. Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. N Engl J Med. 2017 376:1038-1046.

Liu Y, Xu HW, Wang L, Li SY, Zhao CJ, Hao J, Li QY, Zhao TT, Wu W, Wang Y, Zhou Q, Qian C, Wang L, Yin ZQ. Human embryonic stem cell-derived retinal pigment epithelium transplants as a potential treatment for wet age-related macular
degeneration. Cell Discov. 2018 4:50.

Uggenti C, Briant K, Streit AK, Thomson S, Koay YH, Baines RA, Swanton E, Manson FD. Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model. Dis Model Mech. 2016 9:1317-1328.

Taylor RL, Parry NRA, Barton SJ, Campbell C, Delaney CM, Ellingford JM, Hall G, Hardcastle C, Morarji J, Nichol EJ, Williams LC, Douzgou S, Clayton-Smith J, Ramsden SC, Sharma V, Biswas S, Lloyd IC, Ashworth JL, Black GC, Sergouniotis PI. Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease. Ophthalmology. 2017 124:985-991.

Mularczyk EJ, Singh M, Godwin ARF, Galli F, Humphreys N, Adamson AD, Mironov A, Cain SA, Sengle G, Boot-Handford RP, Cossu G, Kielty CM, Baldock C. ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome. Hum Mol Genet. 2018 27:3675-3687.

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