Understanding the mechanism of Sox2 haploinsufficiency on supporting cell to hair cell conversion in the mature mouse cochlea.

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Abstract Hearing loss affects millions of people worldwide and can result from ototoxic medications, recreational or occupational noise exposure, as well as aging; currently, there is no treatment for hearing loss. Recent advances suggest that efforts to treat hearing loss may benefit from a gene therapy approach. However, strategies to promote the regeneration of sensory hair cells in the mature cochlea have yet to provide a reliable therapy for hearing loss. Research initially focused on the hair cell inducing transcription factor Atoh1, which rapidly converts neighboring supporting cells into hair cells in neonatal tissue but has produced limited results in the mature cochlea. More recent evidence supports a multifactor approach that involves the modulation of both hair cell and supporting cell genes within supporting cells. This approach is still limited, as it does not produce cells which resemble normal hair cells. Previous evidence indicated that the loss of one allele of Sox2 results in a haploinsufficient phenotype that produced extra inner hair cells during development as well as enhancing regeneration observed in the neonatal mouse cochlea. This study will extend these findings by using genetically engineered mouse lines to investigate the mechanism of Sox2 haploinsufficiency in the mature cochlea both functionally and genetically. My preliminary data suggests that Sox2 haploinsufficiency promotes the reprogramming of supporting cells into hair cells in the undamaged cochlea after the expression of the hair cell transcription factors Atoh1, Gfi1, and Pou4f3. Aim 1 of this study will investigate whether Sox2 haploinsufficiency can prime supporting cells to respond to these hair cell transcription factors and regenerate lost hair cells. Aim 2 of this study will explore the mechanism by which Sox2 haploinsufficiency promotes the conversion of supporting cells into hair cells by assessing both direct and indirect targets of Sox2 as well as the overall changes in gene expression profiles. To do this, I will perform RNA, ATAC, and CUT & RUN-ChIP- sequencing on purified mature supporting cells to assess the consequences of Sox2 haploinsufficiency.