Investigating the etiology of cholesteatoma

Hearing as one of the five human senses plays a crucial role in our quality of life and integration into society, impacting on speech and language skills. Loss of hearing can be due to defects in the external ear and ear canal; the middle ear, where sound waves are amplified and transmitted from the outer to the inner ear; and the inner ear, where hair cells process the sound waves and convert to neural inputs. Defects in the middle and outer ear lead to conductive hearing loss, while defects in the inner ear lead to sensorineural hearing loss. This application focuses on the middle ear and in particular a relatively common disease that affects this part of the ear known as cholesteatoma. Cholesteatomas are destructive and expanding growths in the ear. These growths are not cancerous but as they expand inside the middle ear cavity they start to destroy the middle ear tissue around them, leading to often severe hearing loss. The only current method of treatment is surgery to remove the tissue but unfortunately the cholesteratomas often reoccur. In severe cases, where damage to the ear is too great, reconstruction of the bones of the middle ear is needed, or a bone-anchored hearing aid is implanted to bypass the defects in the middle ear. In very extreme cases in the absence of surgery these growths can expand into the brain, leading to death. Surprisingly, given the serious nature of cholesteatomas, very little is known about how they initiate. It has been suggested that cholesteatomas develop from outpocketings of the ear-drum, and, in keeping with this, the cysts are often associated with the ear-drum and are made of keratinised tissue. In this project we aim to study how choleateratomas form by concentrating on the question of why they develop only in certain parts of the ear-drum. We will use a combination of analysis of ear-drum development in mice and in human embryos, complemented by analysis of gene changes in cholesteatomas removed from patients during surgery. We aim to use the latest cutting edge techniques to follow cells as the ear-drum forms and to understand how the ear-drum heals after damage. The aim of the project is to gain a better understanding of cholesteatomas to identify novel ways to prevent their occurrence and to reduce their damaging impact on the ear.

Cholesteatomas are invasive middle ear cysts. Acquired cholesteatomas appear to form from retraction pockets in the tympanic membrane and several theories have been suggested to account for their initiation. These cysts form associated with very specific regions of the tympanic membrane, suggesting some underlying developmental differences. We aim to investigate the development of the tympanic membrane, the mechanics of different parts of the membrane and the difference between cholesteatomas that form in different areas of the membrane, using a range of cutting edge techniques in mouse and human.

Aim1: To understand the development of the pars flaccida and pars tensa during mouse and human development

Aim 2: To understand differences in mechanical properties of the murine tympanic membrane in different parts of the ear in culture

Aim 3: To identify differences between cholesteatomas that form in different parts of the ear

Methods:
Transgenic reporter mouse lines will be used to trace the contribution of cells of different tissue origin, and of specific structural genes. Ears will be imaged using confocal and multiphoton microscopes and using optical projection tomography to generate 3D images. Tissue culture of tympanic rings will be used to assess different properties of the tympanic membrane, using time-lapse photography to follow cell movement. Lastly RNAseq will be utilised to identify differences between cholesteatomas that develop in different parts of the ear.

This research is driven by recent advances in the field of ear development, which open up a whole new previously unappreciated avenue of research. The proposed research is novel and directly related to understanding the underlying causes of disease. All the mouse lines needed are available and the questions asked are driven by real clinical problems. The proposal is likely to make clear advances in the field, helping to understand the mechanisms behind a debilitating ear problem.

Who will benefit from this research?

In addition to the academic beneficiaries the intention is that this research will also benefit a wider audience including ENT surgeons and their patients.

How will they benefit?

With less well-known diseases such as cholesteatoma, patient charities providing support in the form of forums, groups and leaflets are indispensable to patients. We aim to engage with charities such as the International Cholesteatoma Association (ctoma.org.uk) and use such platforms to disseminate our research updates and findings to patients in an appropriate manner.
This will provide patients with increased information about cholesteatomas helping them understand their condition and the reasons why they suffer from this problem. Our research will therefore impact on patients and their understanding of their disease.

The ultimate aim for the research is that the results should be integrated into clinical practice. For example, changing surgical planning and procedure to reduce currently high rates of recurrence or the creation of preventative treatments/interventions to halt the growth of cholesteatoma. In the long term therefore there is a real possibility of this work contributing to national health.
In a shorter term this research will emphasise whether there are important differences in cholesteatomas that form in different parts of the year, which may help to inform surgeons how to tackle cysts originating from different locations.

The Fellow will also benefit hugely from being given this opportunity to study for a PhD and take time out to concentrate on research. This will be an important part of her training, and will provide key insight to how to tackle research when she progresses as a surgeon.