Cellular and Molecular Pathways for Hearing Restoration in the Adult Inner Ear

National Institute On Deafness And Other Communication Disorders

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Abstract

A significant goal of the Auditory Development and Restoration Program is to investigate the underlying basis for hearing instability (HI) disorders. Human temporal bone studies demonstrate endolymphatic hydrops, which is an expansion of the endolymph-containing scala media of the cochlea, in some patients with HI disorders. This suggests that an underlying issue related to cochlear ionic homeostasis may be involved in HI disorders, but the underlying mechanisms remain poorly characterized. One location in the cochlea where regulation of ion homeostasis is prominent is the stria vascularis. The stria vascularis (SV) is housed in the lateral wall of the cochlea and consists of 3 layers composed predominantly of marginal, intermediate, and basal cells, respectively, but also includes rare cell types, including spindle cells, macrophages, and pericytes. The SV plays a significant role in inner ear ion homeostasis and generates the endocochlear potential (EP) which is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Adding to our previous work characterizing the transcriptional diversity of the stria vascularis (Korrapati et al., Front Mol Neurosci, 2020), we have characterized the transcriptional profile of rare spindle cells in the stria vascularis (Gu et al., Sci Rep, 2020) that have previously been implicated in hearing fluctuation (Ito et al., 2014). Raw data from this work has been deposited at GEO (GSE152551) and the data is also accessible to the public on gEAR at the following permalink (https://umgear.org/index.html?layout_id=5ba5d060) along with our previously published datasets. We have also recently utilized SV single cell transcriptional profiles to identify potential cellular targets for Menieres disease, a more common hearing instability disorder (Gu et al., Front Neurol, 2021). In the last year, in line with our goal of identifying phenomic features that distinguish individuals with hearing instability disorders, we have established a clinical protocol to perform deep phenotyping of these patients (https://clinicalstudies.info.nih.gov/protocoldetails.aspx?id=000141-DC). Deep phenotyping measures that are being employed include, but are not limited to, standard and novel audiometric tests, contrast-enhanced delayed FLAIR MR imaging, and immunophenotyping. We have begun active recruitment for this protocol. In parallel, to investigate the possible basis for hearing instability in a mouse model, we have made use of Slc26a4-insufficiency mouse model in which alterations in spindle cells have been implicated in hearing fluctuation, to transcriptionally profile the stria vascularis in the setting of hearing instability. We seek to define underlying regulatory networks responsible for hearing instability in these generated datasets and analyses of these data is ongoing. Finally, we have developed novel methods for annotating single cell and single nucleus transcriptional profiles and have begun to validate the importance of gene regulatory networks associated with the onset of the endocochlear potential. We have also nearly completed characterization of an intermediate cell-specific fluorescent reporter BAC transgenic mouse line. Due to the COVID-19 pandemic, work on these projects has been delayed but we expect to publish these data in the next year and make these resources available to the wider scientific community for use.