Research Project Leaders

Litao Tao

Transcription factor POU4F3 is indispensable for the differentiation and homeostasis of sensory hair cells, the essential cell type converting mechanical vibrations into electrical signals for hearing function. During hair cell differentiation, the pioneer factor activity of POU4F3 is required for ATOH1 to access many inaccessible elements to up-regulate hair cell genes. In mature hair cells, reduction of POU4F3 transcription activity due to mutations in one allele leads to hair cell death and hence progressive hearing loss (DFNA15,autosomal dominant non-syndromic hearing loss 15). It remains unclear how the expression of POU4F3 gene is regulated at different developmental stages and there is no feasible method to stimulate the POU4F3 gene in a cell type-specific and temporal-regulated manner. Using mouse models, we plan to investigate the regulatory roles of Pou4f3 enhancers to understand the transcription regulation of the Pou4f3 gene. In addition, we will epigenetically manipulate Pou4f3 enhancers to stimulate Pou4f3 expression specifically in hair cells for a potential therapeutic treatment of hearing loss in DFNA15 patients. Through this proposed study, we will gain a better understanding of how POU4F3 gene is regulated at the transcription level, and potentially find a therapeutic approach to treat DFNA15 patients.

Justine Renauld

Ménière’s disease (MD) is characterized by symptoms such as hearing loss and vertigo, but its underlying cause is still unclear. Research on the temporal bones of MD patients has identified a condition known as endolymphatic hydrops, marked by an expansion of the scala media, indicating a disruption in fluid balance within the inner ear. Endolymph, a vital fluid within the membranous labyrinth, is essential for maintaining hearing and balance. However, the mechanisms that regulate this fluid are not yet fully understood. Given the critical role of fluid homeostasis in the inner ear, our research aims to investigate the formation of endolymphatic hydrops and its impact on neuronal dysfunction.

In this research, we will investigate inner ear dysfunction in an animal model of endolymphatic hydrops. We will correlate hearing and balance thresholds with the ionic and protein composition of endolymph and perilymph. We will test if there is degradation of the blood endolymph barrier during development of endolymphatic hydrops. Finally, we will conduct transcriptomic analysis on the hydropic neurons to better understand the cause of neuronal dysfunction during the development of endolymphatic hydrops.

These studies are essential for comprehending potential mechanisms underlying disruptions in inner ear homeostasis and the development of conditions like MD. This understanding will be essential in developing targeted therapies for MD and related conditions.