Targeting Nitrative Stress for Mitigating Hearing Loss Induced by Concurrent Ototraumatic Exposures
Abstract
This proposal will develop a novel approach targeting the treatment of auditory synapse defects, an FY21 HRRP focus area. Auditory synapses are neural connections between hearing cells, which are critical for hearing signal transfer from the ear to the brain. Hearing cells and auditory synapses are vulnerable to a variety of insults, including blast, traumatic brain injury (TBI), Jet Propellant 8 (JP-8), ototoxic drugs, aging, and infections such as COVID-19. Auditory synaptopathy is damage to auditory synapses. Injuries to hearing cells have been extensively investigated. However, auditory synapse and synaptopathy remain largely understudied areas. Auditory synaptopathy does not affect hearing function thresholds. However, auditory synaptopathy makes complicated auditory tasks such as speech recognition much harder in a noisy environment, which affects the daily activity of millions of military Service Members, Veterans, and the American public. Currently, knowledge of auditory synaptopathy is very limited, and there are no therapeutic interventions. Therefore, there is a critical need to study auditory synapses and synaptopathy. The objectives of this proposal are to determine the molecular mechanism critical for adult mouse auditory synapse integrity and develop therapeutic approaches to treat synaptopathy. To achieve these objectives, we will investigate two scientific aims in this proposal. In the first aim, we will identify the gene and protein that are critical for maintaining the integrity of adult mouse auditory synapses. The second aim will develop surgical approaches to deliver small molecules into the mouse inner ear to rescue auditory synaptopathy. We will use physiological and biological techniques to evaluate the hearing function and auditory synapses in these two aims. The short-term impact of this proposal is that we will characterize adult mammalian auditory synaptopathy, which is an important but largely understudied area. Second, the results of this proposal will advance knowledge of the molecular mechanisms critical for the integrity of adult mammalian auditory synapses. Third, this proposal will determine the extent that the small molecules rebuild the structure and function of auditory synapses, which has not been studied previously. Additionally, auditory synaptopathy could be the early common onset damage in a variety of hearing disorders; therefore, outcomes of this proposal may be used to develop therapeutic interventions for various hearing dysfunction, including hidden hearing loss and tinnitus. The long-term impact is that outcomes of this proposal will be translated into clinical trials, which will open new avenues to develop novel treatment options to benefit deafness patients in two ways. First, the results of this project will be applied to treat auditory synaptopathy patients. These patients may have normal hearing function thresholds but report problem hearing in difficult hearing conditions, which is usually seen in blast-exposed and TBI military Service Members and Veterans. Second, this research is essential for and complementary to other studies targeting hearing pathway restoration. For instance, this research will provide insights into auditory synapse regeneration between newly produced hearing cells in regenerative medicine. Additionally, completion of this proposal will potentially enhance hearing signal transfer from the ear to the brain, which will likely promote the efficacy of the cochlear implant and subsequently improve the hearing experience of cochlear implant patients. Taken together, the success of this work will significantly promote hearing cell reconnection and hearing pathway rehabilitation, which will potentially affect the state of hearing research in today s experience on speech recognition, communication, wellness, and quality of life for active-duty military Service Members, Veterans, and the American public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210827
Entities
People
- Samson Jamesdaniel
Organizations
- United States Army
- Wayne State University