Hereditary hearing loss is a frequent disorder, affecting about 1 in 1,000 babies. Analyses of mouse models of human hereditary hearing-loss cases have revealed that most deafness-causing mutations are associated with the death of mechanosensory hair cells in the hearing organ. These hair cells are essential for hearing, and they cannot regenerate spontaneously in humans, mice, and other mammals. Gene specific therapies are currently not available for non-syndromic hereditary deafness, and treatment options are limited to hearing aid and cochlear implants. We use gene discovery approaches to find ways to prevent gene mutation-associated hearing loss in mouse models of human deafness cases. Specifically, we identify genes that are critical for hearing, and we analyze the molecular functions of the encoded proteins to reveal therapeutic interventions that could compensate for the defects of the studied proteins (Figure 1). Of the genes that are required for hearing, we are especially interested in those that encode transcription factors. Some of these transcription factors will potentially be useful, perhaps as components of a “molecular cocktail”, to overcome the gene regulatory barriers to hair cell regeneration in the hearing organ. Another group of regulatory proteins studied in our lab includes tissue-specifically expressed splicing factors; these factors can alter the exon compositions of specific mRNAs. We identify the exons that are regulated by these splicing factors, and we examine the physiological effects of the regulated splicing changes. Given that the splicing of many mRNAs is regulated similarly in hair cells and neurons, our research branches into the field of neuroscience.
Figure 1. F-actin-stained preparations of organs of Corti from a wild-type mouse (WT), a mouse that models human DFNA27 deafness (Rest+/ΔEx4), and a Rest+/ΔEx4 mouse that was injected with the drug Vorinostat (Rest+/ΔEx4 + Vorinostat). The images indicate that Vorinostat improves hair cell survival in Rest+/ΔEx4 mice. See more details about the experiment in PMID: 29961578.