Hair cells of the inner ear are the primary receptors of the auditory system. They transduce mechanical information, associated with sound waves, into electro-mechanical (outer hair cells) and electro-chemical (Inner hair cells) signals, which lead to amplification of the initial signal and activation of afferent neuronal fibers, respectively. While hair cells and neuronal fibers appear before birth in mice, development and maturation of the hair cells, neurons and synapses proceeds until hearing onset, ~postnatal day 12. This process is believed to be dynamic and modulated by hair cell activity. In particular, recent work has shown that lack of hair cell transmission, due to absence of functional synapses or defective mechanosensation, leads to altered neuronal maturation and specification. Successful outcomes for new therapies, including gene therapy, aimed at restoring hair cell function after birth, may depend on restoration of auditory circuits, including mature and functional hair cell synapses and neuronal fibers. Here we propose to assess how disruption or loss of sensory transduction in several mouse models affects hair cell function, synaptic maturation and spiral ganglion specification. Furthermore, we will determine if inner ear gene therapy is capable of reversing any of these observed changes and identify the conditions for optimal recovery of auditory function. We will combine state-of-the-art technologies to address these important questions, including high-resolution imaging, electrophysiology, single cell RNA sequencing and localization of RNA transcripts.

Public Health Relevance

Development of hearing in human begins embryonically and continues throughout the first few years of life, but how the sensory cells of the inner ear develop proper connections with the brain is poorly understood. We seek to understand how functional development of inner ear sensory cells leads to formation of synapses, maturation of neurons and transmission of sound information. This information may facilitate restoration of hearing in patients with genetic hearing loss.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Freeman, Nancy
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Boston Children's Hospital
United States
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