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MRC DiMeN Doctoral Training Partnership: Deciphering mechanisms underpinning age related auditory neuropathy


MRC DiMeN Doctoral Training Partnership

Sheffield United Kingdom Biochemistry Bioinformatics Data Analysis Genetics Molecular Biology Neuroscience Statistics

About the Project

Background: Age-related hearing loss (ARHL), which causes the progressive loss of hearing sensitivity, is the most common sensory deficit in elderly. Approximately 14.5M people in the UK will be affected by ARHL by 2030. Recent studies, in both mice and human, have shown that the most vulnerable elements to ageing are the auditory afferent fibers or spiral ganglion neurons (SGNs). SGNs are heterogeneous; they differ morphologically, physiologically and in their vulnerability to ageing. Neuronal hearing loss can’t be repaired with the available therapeutic options, hearing aids and cochlear implants, both of which require healthy SGNs. Recent developments in inner ear gene replacement have highlighted promising alternative treatments. However, these approaches rely on good understanding of the molecules responsible for the susceptibility of SGNs to ageing.


Aim: Any ageing process encompasses several physiological alterations involving energy production (mitochondria) and biochemical changes. In this project we aim to identify crucial mechanisms leading to ARHL by investigating mitochondrial gene expression and function and DNA damage in the different types of auditory neurons during ageing. Studies from our group suggested that disruption of mitochondrial DNA repair impacts gene transcription and function. Interestingly, Xpa-deficient mice and human patients, which are defective in DNA repair, exhibit progressive hearing loss caused by progressive loss of the SGNs. Here we hypothesize that progressive accumulation of nuclear and mitochondrial DNA breaks play a key role in the premature death of SGNs and the development of neuronal ARHL.


Training: To assess this hypothesis the student will be using our recently generated transgenic mouse that labels different types of SGNs to sort at the single neuron level from young and compare them to ageing mice. Addressing this multi-disciplinary project will require the student to perform state-of-the-art techniques such as in vivo physiology, single neuron genomic and transcriptomic, mitochondrial bioenergetic measurements and immunochemistry. These experimental approaches, combined with large data analyses for mapping DNA breaks will allow the student to measure functional and molecular changes in the different types of SGNs from ageing compare to young mice. These studies will advance our understanding of the DNA repair mechanisms underlying neuronal progressive/ARHL and would be used in the future to develop diagnostic tools and therapeutic interventions in humans.


Environment: The research outlined will be carried out at the University of Sheffield (UoS), where both the primary and secondary supervisors are conveniently located within the same building. The supervisors are also members of the Neuroscience and aging institutes at the UoS and have several established collaborations. The student will greatly benefit from these established collaborations and interactions with outstanding scientists within and outside UoS.


Supervisor websites:
https://www.sheffield.ac.uk/biosciences/people/mbb-staff/academic/sherif-el-khamisy
https://www.sheffield.ac.uk/biosciences/people/bms-staff/academic/mirna-mustapha


Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:
https://bit.ly/3lQXR8A

Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website

Studentships commence: 1st October 2021

Good luck!

References

1) Fielden J, Wiseman K, Torrecilla I,…El-Khamisy SF, Ramadan K (2020). TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nature communications, 11:1274.

2) Walker C, Herranz-Martin S…..El-Khamisy SF (2017). C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nature Neuroscience. 20: 1225-1235.

3) Fiorella C. Grandi, Lara De Tomasi and Mirna Mustapha (2020). Single-Cell RNA Analysis of Type I Spiral Ganglion Neurons reveals a Lmx1a population in the cochlea. Front. Mol. Neurosci.

doi: 10.3389/fnmol.

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