Discovering function of novel signalling pathway in the mammalian cochlea: implications in health and disease

According to the WHO, 5–10% of the world population suffer from irrecoverable hearing loss due to intense sound exposure, ototoxicity, disease, age and genetic disorders. The primary pathology of hearing loss includes damage to the sensory cells of the inner ear in the organ of Corti. Calcium (Ca2+) ions act as a fundamental chemical messenger for the delivery of information about sound from the inner ear Organ of Corti to the higher brain centres, in the form of nerve impulses. Intense sensory cell electrical activity, which is spontaneous during development and evoked by sound stimulation in mature cells, is anticipated to produce transient focal extracellular Ca2+ changes in the inner ear Organ of Corti. The question of external calcium signalling has never been investigated in the inner ear, while it is known to have multiple functions in the neuronal signalling in the brain, including regulation of synaptic transmission and neuronal activity.

Our preliminary results reveal for the first time a strong expression of the calcium sensing receptor (CaSR) in the Organ of Corti. CaSR is a membrane protein receptor that detects small fluctuations in external calcium and translates these into cellular signals that could affect hearing. The main objective of this proposal is to discover the function of CaSR in the mature and developing auditory system in health and disease, using mouse models. In order to determine the functional role of the CaSR receptor in the process of hearing, we will use mouse models where the CaSR gene has been functionally modified, and characterize any morphological and functional changes within the inner ear and auditory function using molecular, cellular and electrophysiological approaches.

This project is extremely important and timely, as it will elucidate the function of a novel calcium signalling pathway within the auditory inner ear, where calcium signalling already has an unprecedented role in normal hearing. Most importantly, it will provide novel treatment possibilities for the majority of hearing disorders, which are associated with altered Ca2+ homeostasis.

By combining shared resources that different groups can offer, the graduate student will have ample opportunities to learn various experimental techniques, as well as to learn from and network with other colleagues. The student working on this project will become highly skilled at working on cross-disciplinary problems of importance to experimental research, public health, and commercial sectors. They will gain key physiological, molecular and cellular biology, electrophysiology and functional imaging skills. They will be able to apply these skills to a unique set of technically challenging in vivo, in situ, and in vitro measurements of the cochlea and its components, and more widely in the fields of neuroscience and bioscience. Training in career skills, in particular: grant and manuscript writing, will be provided by the primary supervisor and through grantsmanship workshops and other staff development courses offered by the University. The student will attend the Annual Association for Research in Otolaryngology conference to present their research progress, which will contribute to the development and mastery of communication and presentation skills, and provide an introduction to the relevant research community.

The student will work within an interdisciplinary team of experienced physiologists, biophysicists and engineers, which is unique in the world, and with links to an international network of academic, clinical and industrial researchers interested in auditory physiology