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DiMeN Doctoral Training Partnership: Investigating the impact of alternative splicing on retinal cell structure and function: a multidisciplinary study to uncover new regulators of retinogenesis in health and disease

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  • Full or part time
    Dr L Lako
    Prof CA Johnson
  • 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

This is an exciting and timely project investigating how mutations in a pre-mRNA processing factor, PRPF31, leads to development of autosomal dominant retinitis pigmentosa (RP). This is a common form of hereditary, progressive sight loss with a prevalence of about 1 in 2500 affecting more than 1 million people worldwide. Autosomal dominant inheritance accounts for about 40% of RP, and a very recent report estimates that 38% of cases of this RP inheritance type are caused by mutations in splicing factors. To date, there are very few preventative treatments currently available due to a lack of understanding of molecular causes of these conditions. These disorders are both medically challenging and important to diverse fields of basic medical research. Our groups have generated an in vitro disease model that recapitulates key features of RP and will be used to identify the key cellular process and associated proteins that lead to photoreceptor degeneration. This work forms the central aim of this studentship.

The student will join two dynamic teams of researchers located at the Institute of Genetic Medicine at Newcastle University and Institute of Molecular Medicine at University of Leeds. The successful candidate will use state-of-the-art facilities at Newcastle to generate light-responsive functional retinal organoids that will be subjected to proteomic and bioinformatic analysis in collaboration with the Newcastle University Proteome and Protein Analysis core facility. The student will be trained in a broad range of biochemical techniques including pluripotent stem cell culture and differentiation, immunostaining and fluorescence microscopy, quantitative RT-PCR, gene transfection, western blotting and statistical analysis. The student will use cutting-edge super-resolution imaging methods established at the secondary supervisor’s lab to investigate the localization and expression of top candidates identified by the proteomic analysis. The successful applicant must be able to demonstrate a strong background in either biochemistry or molecular cell biology, with an interest in human molecular genetics and a first degree in a relevant biomedical subject. Applicants will be expected to demonstrate that they have the ability and ambition to develop a successful multidisciplinary research project.

Technical training opportunities:
The project will provide excellent opportunities for training in multidisciplinary research methods, all of which are established in the labs of the supervisors:
1. generation of light responsive laminated retinal organoids and RPE cells
2. proteomic analysis of retinal oganoids and RPE cells generated from patient specific iPSC lines and isogenic controls created through the Crispr/Cas9 approach
3. live cell imaging of fluorescently-tagged proteins
3. confocal and super-resolution microscopy
4. image analysis and bioinformatics techniques
5. general molecular biology techniques (PCR, plasmid construct preparation for mammalian cell transfection and expression, sequencing, western blotting etc.)

Funding Notes

This studentship is part of the MRC Discovery Medicine North (DiMeN) partnership and is funded for 3.5 years. Including the following financial support:
Tax-free maintenance grant at the national UK Research Council rate
Full payment of tuition fees at the standard UK/EU rate
Research training support grant (RTSG)
Travel allowance for attendance at UK and international meetings
Opportunity to apply for Flexible Funds for further training and development
Please carefully read eligibility requirements and how to apply on our website, then use the link on this page to submit an application: https://goo.gl/jvPe1N

References

Buskin et al. (2017) Alternative splicing of mRNA processing genes underlines the retinal specific phenotype of retinitis pigmentosa caused by mutations in the PRPF31 gene. Under review (Cell Stem Cell).
Megaw E, Abu-Arafeh H, Mellough C, Gurniak-Witke C, Witke W, Dhillon B, Wright AF, Lako M and Ffrench-Constant C. Human induced pluripotent stem cell and animal models of Xlinked retinitis pigmentosa identify impaired gelsolin activation as a cause of photoreceptor loss. Nature Communications Aug 16;8(1):271. doi: 10.1038/s41467-017-00111-8.
Hallam D, Collin J, Bojic S, Chichagova V, Buskin A, Yu X, Lafage, L, Otten G, Anyfantis G, Mellough C, Przyborski S, Alharthi S, Korolchuk V, Lotery A, Saretzki G, McKibbin M, Armstrong L, Steel D, Kavanagh D and Lako M. An iPSC patient specific model of CFH (Y402H) polymorphism displays characteristic features of AMD and indicates a beneficial role for UV light exposure. Stem Cells 2017, in press.

Chichagova V, Hallam D, Collin J, Buskin A, Saretzki G, Armstrong L, Yu-Man P, Lako M and Steel D. Human iPSC disease modelling reveals functional and structural defects in retinal pigment epithelial cells harbouring m.3243A>G mitochondrial DNA mutation. Scientific Reports 2017, in press.

Wheway G et al. (2015). An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nature Cell Biology 17: 1074-87.
Lambacher NJ et al. (2016). TMEM107 recruits ciliopathy proteins to anchored periodic subdomains of the ciliary transition zone membrane and is mutated in Joubert syndrome. Nature Cell Biology 18:122-31.
Malicki J & Johnson CA (2017). The cilium: cellular antenna and central processing unit. Trends in Cell Biology 27:126-140.



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