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Functional and mathematical modelling of the response to oxidative stress in the ageing retinal pigment epithelium

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  • Full or part time
    Prof L Paraoan
    Prof M Jackson
    Dr D Shanley
    Dr Glyn Nelson
  • 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 project proposes a multidisciplinary approach for studying the decline of vision with ageing. It focuses on a specialised monolayer of cells, the retinal pigment epithelium (RPE), which comes in direct contact with the neuroretina and separates it from the vasculature at the back of the eye. RPE cells ensure rods and cones in the retina are renewed and supplied with nutrients daily throughout life. Due to the intense metabolic rate they sustain, as well as the high levels of light and oxygen they are exposed to, RPE cells are prone to high oxidative stress. Although they are equipped to protect themselves against this stress, their protective anti-oxidant mechanisms decline with ageing and this contributes to the impairment of the overall RPE functions which in turn leads to gradual visual impairment and even blindness.

Understanding the mechanisms through which ageing and oxidative stress lead to changes in normal RPE physiology is essential for developing preventative and therapeutic approaches for ensuring the ageing population can retain effective eyesight. The project will make use of our recent gene expression profiling of RPE cells at different ages and in response to specific age-related stresses known to induce oxidative stress. The aim is to build on this data to create and validate a comprehensive mathematical model of the modulation of RPE functional pathways affected by age-related response to oxidative stress.

The training will ensure development of highly topical skills in data science and computational modelling combined with molecular cell biology and live-cell imaging applied to in vitro cell models of RPE ageing. Specifically, training will encompass mathematical modelling/in silico analysis and transcriptome data analysis, alongside a broad range of core and advanced molecular, cell-based techniques aimed to develop key laboratory-based skills in iPSCs/differentiated cell culture, qPCR, immunoblotting, cloning, flow cytometry and cell imaging. While primarily based in the Ocular Molecular Biology and Mechanisms of Disease Group in Liverpool, the student will benefit from the collaboration with the integrative bioinformatics and computational modelling group in Newcastle, developing skills that will be vital for future Biosciences research. The student will have the opportunity to attend ageing, vision and systems biology conferences benefitting from the groups’ multiple international collaborations.

We encourage students from diverse backgrounds to apply and contribute to the team’s truly inclusive, engaging and supportive culture. Candidates with either a biological and/or computational background are welcome to apply as full interdisciplinary training will be provided.

HOW TO APPLY
Applications should be made by emailing [Email Address Removed] with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to [Email Address Removed]


Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Increased rate of retinal pigment epithelial cell migration and pro-angiogenic potential ensuing from reduced cystatin C expression. Invest Ophthalmol Vis Sci. Accepted November 2019.

CRISPR/Cas9-mediated one step bi-allelic change of genomic DNA in iPSCs and human RPE cells in vitro with dual antibiotic selection. Sci Rep. 2019 9(1):174.

AGE-related modulation of cathepsin L and NF-kB signalling effectors in retinal pigment epithelium leads to augmented response to TNFα. J Cell Mol Med. 2019 23(1):405.

Whole genome methylation profiling of the retinal pigment epithelium of individuals with age-related macular degeneration reveals differential methylation patterns for SKI, GTF2H4 and TNXB genes. Clin Epigen. 2019 11(1):6.

Modelling the role of redox-related mechanisms in musculoskeletal ageing. Free Radic Biol Med 2019 132:11-18
PyCoTools: A Python Toolbox for COPASI. Bioinformatics 2018 34: 3702-3710.

Identification of candidate protective variants for common diseases and evaluation of their protective potential. BMC Genomics 2017 18(1):575.

Molecular habituation’ as a potential mechanism of gradual homeostatic loss with age. Mech Age Dev 2017 169:53-62.

Systems modelling ageing: from single senescent cells to simple multicellular models. Essays Biochem. 2017 61:369-377.

A systems study on amino acid stimulation reveals concurrent activation of AMPK and mTOR converging on ULK1 and autophagy. 2016 Nature Comms 13254.



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