BBSRC White Rose DTP Studentship - Identification of biochemical changes linked to age-related hearing loss and their association with neurological disorders
Prof Walter Marcotti
Prof Sherif El-Khamisy
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
Age-related hearing loss (ARHL) causes a progressive loss of hearing sensitivity, impaired sound localization and decreased ability to understand speech, especially in noisy environment (Gates & Mills, 2005 Lancet 366:1111). ARHL is the most common sensory deficit and third most prevalent chronic medical condition in the elderly, even above diabetes. Approximately half of adults in their 70’s exhibit ARHL severe enough to affect communication. Approximately 14.5 million people in the UK (>500 million worldwide) will be affected by hearing loss by 2030. People affected by ARHL are excluded from basic day-to-day communication, which is associated with significant psychological and medical morbidity, including social isolation and depression. Moreover, there is growing evidence for links between ARHL, cognitive decline and increased risk of dementia and Alzheimer’s disease (e.g. Panza et al 2015 Nature Reviews 11:166; Thomson et al 2017 Laryngo Invest Otolaryngol 2:69). We have shown that increased genomic instability is associated with ARHL and with a number of neurological disorders. However, it is currently unknown whether (and how) ARHL exacerbates cognitive decline or that they share common molecular mechanisms such as defective DNA repair, during aging.
Any aging process encompasses several physiological changes in mice and humans, such as changes in energy production (mitochondria) and biochemical changes at single cell level (Phillip et al 2015 Annu Rev Biomed Eng 17:113). Genes involved in DNA repair during transcription have been linked to age-related neurological disorders including ataxias, dementia and Alzheimer’s diseases (e.g. Walker et al 2017 NatNeurosci 45:1159). For example, Xpa-deficient mice and humans, which are defective in DNA repair, show increased auditory thresholds and loss of afferent neurons compared to control aged mice. Our preliminary data suggest that aged hair cells seem to show a higher level of Prx3 (markers for oxidative stress) and γ-H2AX (DNA damage). Therefore, our hypothesis is that progressive accumulation of transcription-blocking DNA breaks play a key role in the development of ARHL, and as such sharing a molecular mechanism with neurological disorders.
The aim of this PhD project is to identify crucial mechanisms leading to ARHL by investigating mitochondrial function, DNA damage repair, Ca2+ homeostasis in the auditory organ during aging, which have been identified as potential crucial factors leading to ARHL (e.g. Yang et al 2015 Front Cell Neurosci 9:276). Our overarching hypothesis is that progressive accumulation of transcription-blocking DNA breaks play a key role in the development of ARHL.
Addressing the above project will require the student to perform state-of-the-art techniques such as in vivo measurements, mechanoelectrical transduction, immunolabeling and confocal imaging and biochemistry using young and aged mice, combined with large data analysis. The student will greatly benefit from the support of two world-leading PIs in auditory physiology (Marcotti) and DNA damage (El-Khamisy) and from the several postdocs and PhD students currently present in the two research groups.
- a tax-free stipend at the standard Research Council rate (~£15,009, to be confirmed for 2020) for 4 years
- tuition fees at the UK/EU rate for 4 years.
- research costs
At least a 2:1 honours degree in a relevant subject or equivalent. The interdisciplinary nature of this programme means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, students with mathematical backgrounds who are interested in using their skills in addressing biological questions.
Studentships are available to UK and EU students who meet the UK residency requirements. Further information on eligibility: https://www.whiterose-mechanisticbiology-dtp.ac.uk/about-dtp/how-to-apply/.
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