Prevention of auditory nerve degeneration in noise-induced hearing loss

Ralph H Johnson Va Medical Center, Charleston SC

Investigators

Abstract

Hearing loss due to excessive noise exposure is one of the most common military service-connected disabilities. This neurosensory disorder significantly impacts communication abilities, daily duty performance, and quality of life of Veterans. For example, more than 1.3 million Veterans received disability compensation for hearing loss in 2020. Hearing loss also shares significant comorbidity with traumatic brain injury, posttraumatic stress disorder, and depression. Currently, there are no FDA-approved medications for preventing noise-induced hearing loss (NIHL); therefore, investigations are urgently needed to uncover new cellular and molecular mechanisms of NIHL and develop efficient pre-clinical treatment strategies for this common communication disorder. To begin to address this important public health concern, we have investigated the roles of dysmyelination and dysregulation of Quaking (QKI) RNA binding proteins (RBPs) in auditory nerve (AN) degeneration and functional decline following noise injury. The AN is the primary conveyor of acoustic information from sensory hair cells to the brainstem. Approximately 95% of AN fibers are myelinated by glial cells. Noise exposure experienced by service members can lead to loss and/or dysfunction of multiple cell types in the peripheral auditory system, including glial cells of the AN. Glial cell dysfunction occurs immediately after excessive noise exposure and results in demyelination, and alterations in glial-associated paranodal structures at the node of Ranvier, which leads to AN degeneration and auditory function impairment. Our recent study revealed that the integrity of myelin and two types of paranodal structures associated with Schwann and satellite cells is critical for the maintenance of normal AN function. A QKI deficiency in adult mouse glial cells results in loss of myelin, deterioration of paranodal structures, AN dysfunction, and hearing loss. QKI RBP isoforms (including three alternative splicing isoforms QKI-5, QKI-5, and QKI-7) are differentially expressed in mouse Schwann and satellite cells during AN development and myelination. Excessive noise exposure is associated with an upregulation of QKI-7, but not QKI-5 and QKI-6, which may contribute to demyelination (or a fail in remyelination) and AN functional declines. Together, these exciting new observations strongly suggest that QKI RBPs are critical regulators of myelin formation and maintenance in the AN. We hypothesize that manipulation of QKI isoform expression (and their downstream targets) in cochlear glial cells will affect AN maintenance, repair of myelin structures and improvement of auditory function after noise injury. To test this hypothesis, Aim 1 will determine how dysregulation of QKI RBP expression leads to downstream changes that result in demyelination, disruption of nodes of Ranvier and AN degeneration following excessive noise exposure. We will also determine if key QKI targets identified in animal models are present in human AN glial cells using human temporal bones. Aim 2 will determine the extent to which manipulation of expression levels of QKI isoforms and/or key QKI targets can preserve myelin structure and reduce AN degeneration after noise injury. Using well-established animal models and human cochlear tissues, knowledge gained from this translational study will further substantiate the use of QKI RBPs as key therapeutic targets to alleviate noise-induced hearing loss in Veterans.