Regenerating hair cells in the mammalian inner ear: defining conditions in the vestibular sensory epithelia.

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Balance dysfunction results in dizziness and vertigo. It is often disabling and is a significant contributor to falls in the elderly. Dizziness is the most common cause of visits to the GP amongst the elderly population. It is also prevalent amongst those with acquired deafness. One major factor underlying balance dysfunction is the loss of sensory ?hair? cells from the vestibular (balance) system in the inner ear. This study will assess the potential for regenerating hair cells in the vestibular system. Vestibular tissue taken from humans and from young and aged mice will be maintained in culture. A consortium of ENT surgeons across the UK will provide human vestibular tissue, normally discarded during surgery for acoustic neuromas (benign tumours of the auditory nerve). This presents a unique opportunity for direct experimental comparison of inner ear tissues of animals and humans. When hair cells die the supporting cells that surround each one close the lesions. There is some evidence that after loss of hair cells, supporting cells can sometimes convert into hair cells, to replace those lost. This project will compare the capacity to regenerate functional hair cells in these vestibular tissues after insertion of a gene, Atoh1, that is known to induce conversion of supporting cells into hair cells, when delivered to supporting cells by a non-virulent virus engineered to contain it. The project will also assess possibilities for inducing supporting cell conversion by pharmacological manipulation of a biochemical pathway that normally is active during development of the inner ear to regulate the differential fate of precursor cells as hair cells or supporting cells. There is also evidence that the vestibular system of mice contains a small population of stem cells from which hair cells can be generated. The project will examine whether such a population exists in the human vestibular sensory tissues, and if so whether such cells could provide an alternative source of replacement hair cells. Any successful hair cell replacement strategy, however, depends upon the supporting cells that remain after hair cell loss maintaining an environment that will support the survival of functional replacement hair cells. The project therefore will also identify the characteristics of the supporting cell population during recovery after hair cell loss to determine the conditions under which regeneration occurs. Defining the conditions for hair cell regeneration in the vestibular system will lead to clinical treatments for a wide-spread, disabling condition.