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Development of RNA reprogramming tools for tagging genes in Drosophila and human iPS cells


Department of Life Sciences

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Dr T Southall No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

The Department of Life Sciences at Imperial College London has funding for 7 3-year departmentally funded PhD studentships, to commence October 2021. Please see below for the details of the individual projects, 6 of which involve interactions with industry. For information on the individual projects please contact the relevant supervisor as detailed below. For queries about the application and interview process please contact Rozan Hamilton-Nixon at [Email Address Removed]

Application deadline: 12noon, 5 April 2021

Application process: To apply please complete the application form found at https://www.imperial.ac.uk/bbsrc-doctoral-training-partnership/application-process/application-form/[GK1] 

Dr. Tony Southall. [Email Address Removed]

The ability to modify and tag endogenously expressed genes is an essential tool in many areas of academic research and the biotechnology industry. The common and often used approach, CRISPR/Cas mediated homologous recombination, has many drawbacks which include off-target effects, unpredictable locus specific on-target efficiency, potentially unwanted introduction of DNA concatemers, requires laborious clonal isolation followed by thorough genotypic analysis and delivery of CRISPR/Cas reagents. Here, we propose to further develop and optimise an alternative tool that instead reprograms the mRNA, rather than editing the DNA. This method is based on the expression of a pre-trans-splicing molecule (PTM), which is an RNA that binds to the intron of a pre-mRNA (before splicing), leading to trans-splicing to the PTM, which contains the reprogrammed exons. Previous studies, including our own, have validated this method works. However, its general applicability is limited by low efficiency, off-target effects, and leaky translation of the PTM. Here we will test and optimise new modifications that can address these issues. Initial modifications and novel applications will be optimised and tested in Drosophila, allowing for definitive testing for any off-target reprogramming events. These technologies will then be optimised for use in identifying programmable differentiated cell populations from human iPSC cells through our partnership with bit.bio (The Cell Coding Company), Cambridge, UK.


Funding Notes

The studentship will cover UK tuition fees of £4,500pa and will provide an annual tax-free maintenance stipend of £17,609, in 12 monthly instalments. Studentships will be funded for a maximum of 36 months, subject to satisfactory progress. A BSc in biological, or related, sciences is required at Upper Second Class level or better and candidates with a Masters degree, in addition to the BSc, might be given preference. Candidates must be UK nationals although EU candidates with settled status in the UK may be considered. Non UK nationals are not eligible.

References

1. Berger A, Maire S, Gaillard MC, Sahel JA, Hantraye P, Bemelmans AP. mRNA trans-splicing in gene therapy for genetic diseases. Wiley Interdiscip Rev RNA. 2016 Jul;7(4):487-98. doi: 10.1002/wrna.1347. Epub 2016 Mar 28. PMID: 27018401; PMCID: PMC5071737.
2. Trochet D, Prudhon B, Jollet A, Lorain S, Bitoun M. Reprogramming the Dynamin 2 mRNA by Spliceosome-mediated RNA Trans-splicing. Mol Ther Nucleic Acids. 2016 Sep 13;5(9):e362. doi: 10.1038/mtna.2016.67. PMID: 27623444; PMCID: PMC5056991.


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