Middle ear cavitation and mesenchymal clearance: links with deafness and otitis media

As one of the five human senses, hearing not only has critical biological function, but is also crucially important for our integration within society. Worldwide the main cause of mild to moderate hearing impairment in children is chronic middle ear inflammation (otitis media). In the UK around 200,000 children suffer from repeated middle ear infections each year. In the developed world, implantation of ventilation tubes to combat otitis media is the most common reason for surgery in children and is a substantial burden on the healthcare services. Given the number of individuals affected, and the debilitating nature of chronic OM, it is vital that a better understanding of the factors that can influence the onset of OM are addressed.
The abnormal presence of mesenchyme in the middle ear has been shown to be closely linked with chronic cases of otitis media. During normal ear development mesenchymal tissue is lost from the middle ear to create an air-filled cavity. In this grant we wish to study why mesenchyme remains in the ears of some children, using the mouse as a model. We will investigate how the middle ear cavity normally forms, what goes wrong in cases where the mesenchyme is not removed, and will then try and correct this defect. This work will help our understanding of middle ear disease, and aims to initiate new methods to treat problems.

Defects in the middle ear lead to a failure in the conduction of sound from the external ear to the inner ear resulting in hearing loss. In this grant we look at the process of cavitation, whereby the middle ear mesenchyme around the ossicles is cleared to create an air-filled space in which the ossicles can vibrate. Defects in cavitation lead to mesenchyme being retained in the middle ear, which in severe cases leads to deafness. In mild cases the retained mesenchyme does not directly affect hearing but is thought to hamper aeration of the middle ear leading to an increased incidence of middle ear infection (otitis media). Otitis media (OM) is a complex multi-factorial disease characterised by persistent inflammation of the middle ear mucosa. Acute episodes of OM in children are associated with middle ear bacterial infections. In a number of cases, acute OM can lead to recurrent episodes or chronic suppurative OM, causing build up of fluid in the middle ear (OM with effusion). This can eventually lead to erosion of the ossicles and temporal bone and hearing loss. The structure of the middle ear and Eustachian tube, the host immune status and innate mucosal defence and pathogen virulence have all been shown to play a role in the pathogenesis of the disease. Given the number of individuals affected, and the debilitating nature of chronic OM, it is essential that a better understanding of the factors that can influence the onset of OM are addressed.
We aim to study how the middle ear undergoes cavitation using mouse and chick embryos as models. We will investigate the mechanisms responsible for loss of the mesenchyme in normal development, and look at what goes wrong in mouse models with retained mesenchyme. The link between retained mesenchyme and otitis media and the formation of middle ear cysts will be addressed. Finally we aim to correct the cavitation defect in mutant mice. This grant aims to increase our understanding of the causes of deafness and middle ear disease, and may lead to new treatments in the future.