Enhancing Cochlear Proteome Fidelity to Prevent Noise-Induced Hearing Loss
Abstract
The goal of this project is to advance the development of a noninvasive therapeutic strategy to protect U.S. Service Members from noise-induced hearing loss (NIHL). Recently, it was unexpectedly found that many U.S. Service Members suffer from NIHL. Although they perform well on auditory detection tasks, their ability to understand speech in noisy environments is degraded. This mysterious phenomenon, now called hidden hearing loss, represents a major health crisis since it puts U.S. Service Members at an increased risk on the battlefield and reduces their quality of life after returning home. In our preliminary studies on mice, we discovered that exposure to loud noise causes the accumulation of biological molecules (i.e., proteins) within the inner ear immediately after noise exposure. Our results show that this process is due to impaired protein degradation and folding, which induces the selective expression of protein doctors that refold and degrade these substrates. In addition, during the recovery period two weeks after noise exposure, we found that the cellular machinery responsible for synthesizing new proteins was also activated. The rationale is that drugs that regulate protein doctor function can protect the inner ear and prevent NIHL through activation of stress-responsive signaling. Indeed, in our preliminary studies, we have identified several drugs that can protect the cochlea from NIHL. The primary objective of this project is to build on this foundational understanding and our recent results obtained during the Level 1 funding period to advance these efforts toward clinical translation. In our studies, we screened eight commercially available candidates and homed in on two drugs that showed the most promise for preventing NIHL. The benefit of this strategy is twofold. First, by using previously developed drugs there will be only minimal clinical risks since these drugs have already been deemed as safe in cells. Second, because they are already commercially available and fully characterized there should be little delay in repurposing them for NIHL. Thus, for at least one of our strategies, the projected timeline for translation to a patient-related outcome is expected to be short. To maximize the potential impact of our therapeutic strategies, we will test whether they can be used to both effectively prevent NIHL or accelerate the recovery process after overexposure to damaging levels of sound. The hypothesis is that modulating protein doctor activity in the inner ear restores homeostasis and prevents NIHL. While the proposed research will be conducted in mice and cultured cells, the lessons learned and the milestones met represent key steps toward the development of an effective therapeutic strategy for humans. To test this hypothesis, I propose the following two aims: Aim 1: To confirm that that the protein doctor activating drugs are properly functioning in the relevant cells in a predictable manner. Aim 2: To rigorously evaluate the therapeutic potential of activating these protein doctors to prevent NIHL in mice. I expect that this project will significantly advance the field of hearing restoration research in several strategic ways. First, it will provide a new understanding of the therapeutic potential for adapting the protein homeostasis machinery for the prevention of NIHL. Second, optimizing multiple promising therapeutic strategies will substantially advance our efforts toward the timely development of an effective therapeutic minimizing the functional consequences of traumatic exposures. Based on the previous success of other researchers using the same logic for similar diseases and disorders in humans, the proposed strategy is well-positioned to achieve its goals. Ultimately, I anticipate that this project will increase the operational performance and quality of life of U.S. Service Members and the American public at large by reducing the incidence
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210773
Entities
People
- Jeffrey N Savas
Organizations
- Northwestern University
- United States Army