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

National Institute On Deafness And Other Communication Disorders

Investigators

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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. 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 are well into recruitment of 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. Our group’s work with quantitative analysis of delayed FLAIR MRI imaging was recently published (Telischi et al., Sci Rep, 2025). We are also currently working to analyze our immunophenotyping analyses, including FSFC and cytokine profiling, in the cohort of patients who have completed the study thus far. 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 published in Otology and Neurotology on the deep phenotyping of this mouse model (Johns et al., 2024). This published study provides a rationale for our snRNA-Seq investigation of hearing instability in this mouse model. 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. The manuscript for this work is under preparation. Intramural collaborations with the Inner Ear Gene Therapy Program (P.I. Wade Chien, MD) and the Section on Human Genetics (P.I. Thomas B. Friedman, PhD) have resulted in publications on the impacts of gene therapy on the stria vascularis (Ishibashi et al., Mol Ther Methods Clin Dev, 2025) and the mechanisms underlying hearing loss caused by taperin deficiencies (Belyantseva et al., J Cell Biol, 2025), respectively. Extramural collaborations with the Dabdoub Lab at the University of Toronto and a multi-institutional collaboration including the Nelson Lab at Indiana University and the Shearer Lab at Harvard have resulted in publications defining the transcriptional differences that occur between perinatal and adult stria vascularis (Thulasiram et al., iScience, 2025) and the contribution of the endocochlear potential to TMPRSS3-mediated hearing loss (Shearer et al., J Clin Invest, 2025). In addition to the above, we have developed a marginal cell-specific inducible-Cre mouse model which will allow targeted deletion of genes in marginal cells as part of a collaboration with Lijin Dong, PhD at NEI. We have expanded this collaboration to include Alan Cheng, MD (Stanford University), Justine Renauld, PhD (Creighton University), and Thomas B. Friedman, PhD (NIDCD). Work on this mouse model and collaboration is ongoing. We expect that this mouse model will be a resource to the field of auditory research and are leveraging extramural partnerships to share and define this resource more rapidly.