Details
Hearing loss is the most common sensory dysfunction in humans, and it is associated with social isolation and depression. Approximately 1 billion people in the world will be affected by hearing loss by 2050 (World Health Organization). Although the aetiology underlying hearing loss can be quite diverse, genetic mutations cause about 70-75% of congenital deafness (https://hereditaryhearingloss.org/). Currently, there are no treatments for hearing loss and, although beneficial, hearing aids and cochlear implants cannot completely restore hearing. However, recent developments in gene replacement technologies have highlighted promising therapeutic interventions.
Sound is detected by sensory cells, named hair cells, that are located in the cochlea. These cells convert sound waves into an electrical current that is then sent to the brain via afferent fibres, allowing us to perceive sound such as speech and music. However, most of the cells present in the cochlea are glial-like supporting cells. These cells are interconnected by an intricate network of channels that are required for essential physiological processes such as the maintenance of cochlear fluid homeostasis and the supply of nutrients from the blood to the hair cells. These channels, known as gap-junctions, are made from proteins called connexins. Connexins are vital for hearing since nearly half of all cases of hearing impairment present at birth in humans are due to mutations in the genes encoding for connexin 26 (Cx26) and connexin 30 (Cx30) (Mammano, 2019).
The objective of this project is to replace a defective connexin gene with a functional one in a mouse model of hearing loss (Johnson et al., 2017) using AAV-based gene therapy and then investigate the level of hearing function recovery. This proposal will require the student to perform state-of-the-art techniques that are well established in the lab (e.g., Jeng et al., 2022), including in vivo AAV-gene delivery, in vivo animal physiology and several ex vivo approaches such as electrophysiology, immunolabelling combined with confocal imaging and electron microscopy. These experimental approaches, combined with large data analysis, will require the student to think beyond their immediate expertise and will allow them to acquire unique skills that can be transferred to other research fields.
The PhD student will join a highly dynamic Hearing Research group with outstanding expertise in hearing function/dysfunction, and with an excellent track record of training, mentorship, and supervision. The PI is also a leading member of the Institute of Neuroscience, which provides an environment that exposes members, including students, to multidisciplinary interactions across multiple faculties.
Prof Walter Marcotti
@HearingShef
https://www.sheffield.ac.uk/hearing
https://www.sheffield.ac.uk/biosciences/people/academic-staff/walter-marcotti
Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.
Funding Notes
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link:
https://www.sheffield.ac.uk/postgraduate/phd/apply/applying
All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information.
References
References:
Mammano F (2019). Inner ear connexin channels: roles in development and maintenance of cochlear function. Cold Spring Harb Perspect Med 9:a033233.
Johnson et al., (2017) Connexin-Mediated Signaling in Nonsensory Cells Is Crucial for the Development of Sensory Inner Hair Cells in the Mouse Cochlea. J Neurosci 37:258–268.
Jeng et al., (2022) AAV-mediated rescue of Eps8 expression in vivo restores hair-cell function in a mouse model of recessive deafness. Mol Ther Methods Clin Dev 26:355–370.