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Investigation of DNA/RNA Instability in Neurological Disease

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  • Full or part time
    Prof Sherif El-Khamisy
    Dr Guillaume Hautbergue
    Dr F Van Eeden
  • 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

Our genome is constantly threatened by environmental and endogenous stressors. One consequence of this threat is the formation of the rather unusual nucleic acid structures involving a duplex DNA and RNA, called DNA/RNA hybrids (R-loops). We have shown that these structures are pathogenic in the nervous system, causing motor neuron disease and dementia (Nature Neuroscience, 2017; Brain 2018). On the other hand, R-loops are important regulators for gene expression. They form a binding platform at promoters for proteins that modulate repressive modifications, thereby serving as tools to control the activity of genes at the correct time and place. Thus, understanding the mechanisms that regulate R-loop formation and resolution is essential to characterize the mechanisms that control genome integrity, gene expression and disease mechanisms. Although much is known about R-loops from studies in cell culture, we do not currently have the tools to study them at the organismal level. This PhD project will develop an R-loop reporter zebrafish model using an approach that has been validated in cell culture and similar reporter zebrafish models. The student will use this model to monitor R-loops during normal aging but also following exposure to genotoxins. Crossing the R-loop reporter model with other zebrafish lines available in Sheffield that model neurological disorders will serve an excellent tool for drug discovery. It will allow us to study R-loops in different pathological states, at the organismal level. Through their epigenetic regulation, R-loops control many facets of chromatin dynamics and therefore this model will allow us to study multiple biological processes associated with the complex nature of neurodegeneration, such as senescence, inflammation, DNA damage repair, ubiquitin and mRNA nuclear transport.

What will you learn as a PhD student? During the PhD you will perform state-of-the-art techniques in cell and organismal biology related to neuroscience, such as CRISPR-Cas9, live cell imaging, generation of transgenic zebrafish lines, RNA biology and DNA repair techniques. All techniques are well established at the laboratories of the PIs. The student will also use in vivo screening techniques to identify compunds that modulate R-loop levels in relevant disease states.

Why is the research important and timely, yet feasible for you as a PhD student? Understanding the mechanisms controlling R-loops is crucial to effectively modulate their level at the correct time and place. This is important since R-loops underpin multiple neurological diseases and also are important regulators of gene expression. This project is ideal for a PhD student for several reasons:

1) it involves a wide range of state-of-the-art techniques (see above);
2) it will provide an opportunity to generate the first ever R-loop reporter in a living organism;
3) it will benefit from working in well-established and well-funded labs with ample expertise to nurture the student experience;
4) it will challenge the student to think beyond his/her immediate experience, look at the big picture and the importance of achieving the right balance for a biological process to work optimally, and gain training towards becoming an independent investigator;
5) the student will gain multiple transferable skills such as learning how to interpret and write scientific papers, prepare poster and oral presentations for specialist audience and also to the general public via a two-way engagement activities with the public, but also techniques such as CRISPR, transgenesis, confocal and light sheet microscopy.

How will the student contribute to the design of the project? The student will be asked to prepare a detailed proposal within 3-months of the start of the PhD. This proposal, which is an extended literature review followed by a detailed experimental plan and expected outcome, will be presented to a Post-graduate panel. Therefore, the student will initially be responsible to develop their own “design” of the project, which will be discussed with the PIs. Furthermore, as data are generated and analysed their impact on the future direction of the project will need to be assessed, it will be the responsibility of the PhD student to propose options and discuss these with the PIs.

Funding Notes

RCUK equivalent home stipend rate per annum for 3.5 years
Home tuition fees for 3.5 years*
University of Sheffield funded studentships are supported with £6500 for consumables over the course of the award
*Overseas students may apply but need to fund the difference in fees between the home and overseas rate.
A first class or upper second class honours degree in a biological sciences subject or a related discipline, or a merit or distinction in a suitable MSc. Experience working in a research laboratory desirable.

You should be applying to start on a full-time or part-time PhD in October 2020.

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