Genetics and Pathobiology of Deafness

Hearing loss is very common. Around 1 in 2000 children born suffer from a significant hearing impairment that is caused by faults in genes. Most of these faulty genes affect processes in our inner ears that convert sound impulses to signals to the brain that allows us to interpret sounds and to hear. The process is very complex involving exquisitely engineered tissues and we know that many genes must be involved in ensuring that hearing works properly and efficiently. We still know only a fraction of the genes involved. Many of the genes we have identified to date have come from studying mouse models of deafness.||One of the main aims of our research programme is to identify new mouse models of genetic deafness. It is often easier to identify and study genes from mice than to try and identify faulty genes directly in the human population. It is possible to identify mice that are deaf because they fail to show a startle response to loud, high-pitched sounds. Subsequently, we can identify the faulty gene leading to the hearing loss in the mice. Having identified a gene involved with deafness in mice, we can then study the same gene in the human population. Creating a better picture of how genes are involved with hearing can only help us in developing new approaches to treating hearing loss.||Hearing loss can often be caused by Otitis Media (OM), inflammation of the middle ear epithelial lining. OM remains the most common cause of hearing impairment in children and is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population that genes play an important role in whether or not a child develops OM. But we know nothing about the genes involved.||We have recently identified mouse models with OM and have identified the faulty genes. We can now translate these results into the human population and ask whether these genes play a role in human OM. Identifying these genes allows us to understand better why OM occurs and may lead to better approaches to treating the disease.

The work of the Deafness Group has focused on the use of mouse models to identify critical genes involved with the process of auditory transduction and otitis media, in both mouse and humans. Around 1 in 2,000 children born suffer from a significant genetic hearing impairment.
Sensorineural hearing loss affects the process of auditory transduction and in particular the development and function of the sensory hair cells of the cochlea in the inner ear. There are a large number of genes involved with the process of auditory transduction. Over 150 genetic loci involved in non-syndromic deafness have been mapped in human populations. In addition, a large number of mouse loci have been identified affecting hearing. |Otitis media (OM), inflammation of the middle ear mucosal lining, remains the most common cause of hearing impairment in children. It is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population that there is a significant genetic component predisposing to chronic OM, yet nothing is known about the underlying genes involved.
The Deafness Group undertakes research into the genetic and pathobiological mechanisms of deafness within two main themes. First, the group continues its studies of the genetic bases of early- and late-onset hearing loss, identifying the genetic pathways involved and the role they play in hair cell mechanisms and other aspects of inner ear biology. A recent focus has been to understand the genetic pathways involved with age-related hearing loss (ARHL) or presbycusis, providing novel insights into an area for which there is little known about the underlying genetic mechanisms. Indeed we have undertaken a novel ageing screen for mouse mutants involved in age-related hearing loss (ARHL), identifying 7 presbycusis loci, and a number of novel ARHL genes. In addition, we have several collaborators throughout Europe who are engaged in genome-wide association (GWA) studies to identify human presbycusis loci. We share data, providing information on our mouse loci to interrogate their GWA data, and reciprocally we are beginning to generate mouse mutants for human GWA genes to assist in functional validation of these loci. Second, building on the novel mouse mutant models (Jeff, Junbo and Edison) that have been identified at Harwell, we have made substantive advances in our understanding of the genes and molecular mechanisms involved with chronic otitis media (OM). Through the characterization of these OM models we have thrown light on the inflammatory pathways involved, which has led to the development of novel therapeutic routes for OM. Specifically, uncovering the role of hypoxia in chronic OM, we have identified HIF and VEGF signaling pathways as effective targets for therapeutic intervention by VEGFR inhibitors. Moreover, the finding that our OM models are permissive to infection by human otopathogens, such as NTHi, transforms the landscape for studies of infection mechanisms in acute OM and the development of vaccines to treat the acute disease.