This is a Fellowship awarded to Dr Magdalena Zak at University College London in 2021. We are co-funding this project with the Dunhill Medical Trust.
The inner ear houses the cochlea (that contains the hearing organ) and the vestibular system (that governs balance). Both systems contain specialised sensory cells called hair cells – cochlear hair cells detect sound and are the basis of our hearing, while vestibular hair cells detect head movement and orientation and are part of how we maintain our balance. Even though these two types of hair cells share many functional and structural similarities, cochlear hair cells also have specific features that allow them to detect sounds.
Cochlear hair cells are vulnerable to damage from various causes, such as ageing, treatment with certain ototoxic drugs or exposure to loud noise. As they cannot be replaced once they have died, their loss, and the hearing loss that ensues, is permanent. Loss of hair cells is implicated in most forms of hearing loss, and they are therefore a major target of approaches to restore hearing. However, cochlear hair cells are very difficult to grow in a dish or generate from stem cells, making it difficult to study them in more detail; most current protocols in use generate hair cells that are more like vestibular hair cells. To reliably generate cochlear hair cells from stem cells, we need to better understand the molecular processes that tell a developing hair cell in the inner ear whether to become a cochlear or a vestibular hair cell.
Two of these molecular processes centre around proteins called Wnt and Hedgehog – they govern cascades of molecular signals (called signalling pathways) that allow cells to communicate with each other as they develop inside the inner ear. We know that these pathways influence the early formation of both the hearing and vestibular organs, but we don’t know exactly how (or even if) they are involved in controlling which type of hair cell a developing cell becomes.
The aim of this project is to test how the Wnt and Hedgehog signalling pathways are involved in determining whether a developing hair cell becomes part of the hearing or balance system. Magdalena will monitor the activity of both pathways in the developing inner ear to establish when and where they are active, particularly in those parts known to develop into the vestibular and cochlear systems. She will then use genetic tools to interfere with these pathways, to see what happens when they are disrupted. She will then apply this knowledge to stem cell systems to find out if manipulating the activity of Wnt and/or Hedgehog can trigger cochlear hair cell formation.
This project will provide valuable information that will lead towards the development of treatments to restore hearing. The findings could also improve existing methods used to generate cochlear hair cells from stem cells in the lab. Such improvements could accelerate the development of platforms to model different types of hearing loss, to screen potential drug treatments to prevent or restore hearing or silence tinnitus, or to test gene therapies to restore hearing.