Controlling Mitochondrial Dynamics to Mitigate Noise-Induced Hearing Loss
Abstract
Background: The generation of reactive oxygen species (ROS) is one of the underlying mechanisms of noise-induced damage to tissues in the inner ear that leads to noise-induced hearing loss (NIHL). Following loud sound exposure, the generation of excessive ROS by mitochondria in many different tissues of the inner ear is well recognized. Mitochondrial health, size, and shape are maintained by the opposing processes of fusion and fission, events that alter cellular health and energy production. Mitochondrial dysfunction, including the deregulation of fission and fusion processes, is implicated in many human pathological conditions including hearing loss. Inhibition of dynamin related protein 1, the key regulator of the mitochondrial fission process, with the specific small molecule inhibitor mdivi-1 has proven protective in animal model systems of neurodegeneration, retinal ischemia, stroke, and myocardial infarction. One of the major goals of our laboratory is to identify and characterize therapeutic compounds that are effective in reducing NIHL. Objective: The studies proposed here will test the novel hypothesis that inhibiting the mitochondrial fission process will mitigate the deleterious effects of loud sound on hearing sensitivity. In our preliminary studies, we discovered that application of mdivi-1 to the outer ear canal after loud sound exposure significantly reduced noise-induced auditory threshold shifts in our well-characterized mouse model of NIHL. Additionally, protection against loss of auditory hair cells at the high frequency responsive region of the organ of Corti was observed. Importantly, these findings demonstrated that altering mitochondrial dynamics following noise exposure is a potential mechanism for intervention of NIHL. Here, through a pharmacological approach, we propose to define a post-exposure intervention strategy to mitigate a primary cause of loud sound-induced hearing loss: mitochondrial dysfunction and overproduction of ROS. The proposed studies will be carried out in the following specific aims. Specific Aim 1: Determine the optimal dose and dosing regimen for outer ear canal application and intraperitoneal injection of mdivi-1 for mitigation of NIHL resulting from a single steady-state noise exposure. Specific Aim 2: Determine whether inhibition of mitochondrial fission can protect against the adverse mitochondrial-based cellular consequences of loud sound exposure. Specific Aim 3: Determine whether outer ear canal administration of mdivi-1 will prevent the cumulative effects of multiple steady-state loud sound exposures over an extended time period. Study Design: For these proposed studies, we will use the well-characterized CBA/CaJ mouse model, which is extensively utilized in hearing research studies. Two different sound treatment protocols will be used: (1) a single steady-state loud sound exposure that results in both temporary and permanent NIHL and (2) multiple exposures to a steady-state loud sound level that, individually, generates only temporary hearing loss, to assess prevention of cumulative damage and subsequent permanent hearing loss. Controls will consist of vehicle-only treatment. Treatment routes consist of outer ear canal application and post-noise exposure intraperitoneal injection to identify the most effective protocol. Functional tests for hearing capacity will be accomplished by measurement of auditory brainstem responses and distortion product otoacoustic emissions. Molecular and cellular analysis for protection against loud sound-induced damage to tissues of the cochlea will include the assessment of outer hair cells and synaptic ribbon terminal losses as well as markers of cell death in auditory hair cells. Military Benefit: The two most prevalent service-connected disabilities of new and all Veterans for fiscal year 2013 (FY13) were tinnitus and hearing loss, accounting for 35% of the most prevalent disabilities. Further, the n
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510560
Entities
People
- Alfred Nuttall
Organizations
- Oregon Health & Science University
- United States Army