Abstract
Hearing loss is the most frequently reported sensory deficit and affects 1.57 billion people worldwide. It has a significant impact on quality of life. Studies have identified a significant correlation between hearing status and cognitive abilities. Deafness Autosomal Dominant 9 (DFNA9) is a dominant hereditary disorder characterized by a progressive sensorineural hearing loss (SNHL) associated with bilateral vestibulopathy (BV). In this project, the applicant will evaluate hearing, vestibular and cognitive function in (pre-)symptomatic DFNA9 patients and in genetically humanized DFNA9 mice. Based on the statistical analysis of baseline (cross-sectional) data already gathered, the applicant hypothesizes that DFNA9 patients are at significant risk for incident cognitive decline. This application presents a novel approach to identify pathophysiological mechanisms of SNHL, BV and cognitive decline in a genetically engineered mouse model designed to mimic DFNA9 in humans. This model is unique in the field of hearing research and will allow us to investigate the therapeutic potential of any gene editing intervention intended for human use beyond the scope of this application. The expected outcome is important to society because it may identify DFNA9 patients at risk for cognitive decline. Subsequently, it will provide data from a genetically humanized mouse model essential to translate findings from fundamental research to clinically meaningful knowledge and clinical trials.
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