Understanding and enhancing repair of the tympanic membrane

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Hearing as one of the five human senses is important not only for communication but also for our quality of life and integration into society, impacting on speech and language skills. We are able to hear due the unique and complex hearing organ that is the ear. The ear is divided into three parts, the external ear (pinna and ear canal), middle ear, with its three little bones, and inner ear, where the hair cells sense vibrations and transfer information to the brain. In between the external and middle ear sits the ear drum, a thin transparent membrane that converts sound waves into vibrations. This membrane is very susceptible to damage caused by ear infections, pressure changes or head trauma. Its thought that 30% of children will suffer from breaks in their ear drum caused by acute ear inflammation (glue ear or otitis media). Most holes in the membrane heal rapidly without any intervention. Some holes, however, do not heal leading to ear pain, ringing in the ears (tinnitus), ear infections, and hearing loss. These perforation that fail to heal are called chronic and may be due to the size or position of the initial damage, or the presence of infectious agents. Such chronic perforations have to be corrected using surgery with tissue from elsewhere in the body grafted into the ear to bridge the gap.How the ear drum is able to heal is unclear. It has been proposed that adult stem cells reside in the ear and are able to aid in regeneration and healing of holes. Research suggests that these stem cells are located in distinct parts of the ear drum, at the border (the annulus) and in the centre where the ear drum meets the middle ear bones (manubrium). Addition of stem cells, or signaling molecules that can stimulate repair pathways have been suggested as potential treatment for chronic perforations.We plan to use modern imaging techniques, transgenic mouse models, and novel culture techniques to address some of the questions surrounding repair of ear drum perforations. The lead applicant, Prof Tucker, is an expert on the middle ear, while her collaborator, Prof Paul Martin, provides his experience of epithelial wound healing, to create a unique research project that tackles a serious clinical problem.We first aim to determine the mechanisms at play during repair by following stem cell populations and their progeny in the ear after injury, and by perturbing some of the processes (cell migration, proliferation, vascularization) that are thought to play a role in repair. This will be followed by an analysis of the signals that control the ear drum stem cells, concentrating on the role of Wnt signaling. Wnts are a family of signaling molecules with essential role in stem cell maintenance and repair in many other tissues in the body. Wnt activity is found in the putative ear drum stem cell niche but nothing is currently known about the role of this pathway in the ear drum. We will look at the effect of enhancing and inhibiting Wnt signaling on the ability of the ear drum to heal.Finally we will use our explant culture model to understand how current therapeutics, such as topical application of Fgf2, actually work. The project takes a new approach (explant culture of the ear drum) to allow visualization of the ear as it heals and aims to provide the groundwork to create new and innovative ways to prevent chronic perforations in the future.