Eleanor Brown is a PhD student in Professor Dan Jagger’s lab at University College London. Her PhD studentship began in 2023. We are co-funding this fellowship in partnership with the Anatomical Society.
Background
Neurofibromatosis type 2 (NF2) is a genetically inherited syndrome that affects around 1 in 30,000 people. The main hallmark of NF2 is slow-growing tumours within the nervous system, but there is also evidence that there are other effects on the development of the nervous system.
Most people with NF2 develop benign tumours called vestibular schwannomas on the nerves which connect the inner ear to the brain. These tumours cause hearing loss, tinnitus, and balance problems. Evidence suggests that people with NF2 may lose inner ear nerve cells early in their lives, making these sensory problems permanent. NF2 can also affect vision and cause facial paralysis, limb numbness, and a build-up of fluid in the brain that can be fatal.
Despite this, there are currently no approved treatments that target the underlying biology of the syndrome. Antibody therapies that target the tumours show some success in stabilising the disease but often have significant side-effects. Surgical approaches to remove the tumours cause unavoidable damage to nearby nerves that are important for hearing and balance and also for muscle control in the face.
We need to better understand how genetic mutations that cause NF2 affect the structure and function of the nervous system. This will help us to design and develop treatments that can control the growth of the tumours and prevent the life-changing effects of NF2.
Aims
Using a genetic mouse model of NF2, the student will identify the cells in the nervous system that are most likely to be affected by gene mutations linked to the disease. They will also examine the fine anatomical structure of nerves in the inner ear before tumour growth occurs and determine whether the genetic changes associated with the disease affect the development and function of nerve cells in the auditory nerve.
Looking at older NF2 mice, the student will examine how inner ear tissues are affected by tumour growth. They will particularly focus on understanding whether sensory hair cells survive and looking for increased signs of inflammation as the disease progresses.
The student will also compare their findings from the mouse model to samples of inner ear tissue taken from people with NF2 to determine whether the NF2 mouse model replicates the disease processes seen in people. This will help to establish the mouse model as a platform for testing future drug therapies for NF2.
Benefit
The results from this project will lead to a better understanding of how the inner ear changes in people with NF2. This will help to explain why people with NF2 experience a range of sensory problems and determine how much these problems are due to tumour growth alone, or if there are other processes that occur earlier in the disease.
By analysing inner ear cells in NF2-affected people and mice at the molecular level, the student will be able to identify targets for new drug-based therapies for NF2. The results may ultimately also lead to the development of gene therapy strategies to treat NF2 in the future.
More generally, the findings will provide insight into nerve cell development and survival and provide more information about a collection of conditions known as neuropathies that can affect our hearing and balance.