Transcription factors for promoting sensory hair cell differentiation

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Partial or complete deafness is a condition that will affect most people in time. The majority of deafness results from loss or damage of the sensory receptor cells in the inner ear, called hair cells. Once lost or damaged, mammals including humans are not able to regenerate these hair cells. There is much interest in finding ways to stimulate the inner ear to regenerate new hair cells (a process that occurs naturally in other animals such as fish and birds). The key to this is to take lessons from our understanding of the mechanisms that generate hair cells in the developing embryo. These lessons might then be applied to therapy. For example, gene therapy may be used to trigger adult hair cell regeneration directly, or cell therapy may be used in which hair cell formation is triggered in stem cells that could then be transplanted into the inner ear.Our research aims at understanding mechanisms of hair cell formation in normal development. Already, much research has been aimed at a gene called Atoh1, which produces a 'master regulator' factor that triggers hair cell formation during development; it has even been shown in animal models that Atoh1 gene therapy can induce partial regeneration of hair cells, at least in young animals. It is widely believed that Atoh1's ability to promote the generation of hair cells is dependent on other unknown 'cofactors' within the cells of the developing ear, and that lack of such cofactors restrict its function in the adult ear. Our previous work has led to the identification of promising candidates for these cofactors. We propose to show that these cofactors are required for Atoh1's function, and then to apply this information to stem cell culture systems to determine if they can help Atoh1 to trigger hair cell formation efficiently.Our research will be conducted in mouse stem cells and in zebrafish as they are convenient, relevant and well characterised models for these kinds of analysis. If successful, our findings will be applicable to human stem cell studies, leading to potential new therapeutic routes. There are also more immediate benefits to establishing protocols for hair cell formation in stem cells. Stem cells provide a source of specialised cell types in the lab that can be used for modelling disease and for testing the effects of drugs. For instance, skin cells could be taken from patients suffering from hearing diseases and lab protocols used to convert them into hair cells in a dish. These could then be studied to determine the nature of the disease and could be used to screen for therapeutically useful drugs. Overall, our research has the potential to lead to discoveries that facilitate gene therapy, stem cell therapy, and the production of lab models for disease and drug screening.