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

National Institute On Deafness And Other Communication Disorders

Investigators

Linked publications, trials & patents

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. Blending our work in the lab with the growing work on our clinical protocol, we have used publications to draw parallels between stria vascularis and other cochlear cell types with hearing instability disorders including Menieres disease (Gu et al., Front Neurol, 2021), SSNHL (Nelson et al., Otol Neurotol, 2021), and autoimmune and autoinflammatory inner ear disease (Samaha et al., Curr Opin Otolaryngol Head Neck Surg, 2021) and have sought to connect relevant cochlear cell types with transcriptional responses to systemic and intratympanic steroids (Nelson et al., Front Neurol, 2022). Since establishing a clinical protocol to perform deep phenotyping of patients with hearing instability disorders (https://clinicalstudies.info.nih.gov/protocoldetails.aspx?id=000141-DC), recruitment continues to proceed at the anticipated pace. We have also begun to recruit healthy volunteers with repeated imaging for comparison to our patients with hearing instability disorders. 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, including the use of full spectrum flow cytometry (FSFC), cytokine profiling, and proteomics. We have optimized imaging and semi-automated segmentation and image analysis workflows to quantify endolymph compartment volume and are correlating changes in compartment size with phenomic measures. 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 have identified distinct transcriptional profiles in cochlear cell types associated with hearing instability. We have identified underlying regulatory networks potentially responsible for hearing instability and have identified druggable targets and related repurposable therapeutics which we are evaluating for their ability to ameliorate hearing instability. While delayed by COVID-19, a paper on an intermediate cell-specific fluorescent reporter BAC transgenic mouse line developed in the lab has been submitted for publication. Finally, we have developed deep learning and machine learning methods for analyzing large clinical datasets and are employing them through our clinical protocol as well as through collaborations.