Developing Therapeutic Approaches Targeting Spiral Ganglion-Cochlear Nucleus Synaptopathy
Abstract
This proposal will develop a novel approach targeting the treatment of auditory synapse defects, a Fiscal Year 2022 Hearing Restoration Research Program 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 noise/blast, traumatic brain injury (TBI), Jet Propellant 8 (JP-8), ototoxic drugs, aging, and infections. Auditory synaptopathy is damage to auditory synapses. Currently, injuries to hearing cells have been extensively investigated. However, central auditory synapse and synaptopathy remains a challenging research area. Central auditory synaptopathy does not affect hearing function thresholds. However, central 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 civilian patients. Currently, knowledge of central auditory synaptopathy is very limited, and there are no therapeutic interventions. Therefore, there is a critical need to study central auditory synapse and synaptopathy. The objectives of this proposal are to determine the molecular mechanism critical for adult mouse central 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 central auditory synapses. The second aim will develop surgical approaches to deliver small molecules into the mouse to rescue central auditory synaptopathy. We will use physiological and biological techniques to evaluate hearing function and central auditory synapses in these two aims. To achieve the research aims of this proposal, several innovations/improvements have been developed. First, we will study central auditory synaptopathy, an important yet largely understudied field. Second, we will investigate the role of a small molecule in adult mouse central auditory synapse integrity, which is conceptually innovative. Third, the small molecule will be supplied to an auditory synaptopathy animal model to determine its role in rescuing synaptopathy in vivo. Finally, a unique complementary combination of transgenic mouse, in vitro neuronal co-culture, and in vivo inner ear surgery approaches will be utilized to test the hypothesis of this proposal. These innovations/improvements are necessary for the completion of the proposed research aims. The short-term impact of this proposal is that we will characterize adult mammalian central 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 to which the small molecule rebuilds the structure and function of auditory synapses, which will guide the development of a specific treatment strategy. Finally, results of this proposal will be applied to determine the role of the small molecule in age-related and noise-induced synaptopathy and study if the small molecule rescues age-related and noise-induced synaptopathy in our future proposals. 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 hearing loss patients in multiple 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 noise/blast exposed and TBI military Service Members and Veterans
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310684
Entities
People
- Zhengqing Hu
Organizations
- United States Army
- Wayne State University