The mouse cochlea harbors only 800 inner hair cells and about three times as many outer hair cells. This low number of cells has hampered progress specifically in the study of the molecular biology of inner ear cells. The use of single hair cell gene expression profiling has the potential to turn this disadvantage into a major advantage because it allows for oversampling the organ by generating high resolution quantitative gene expression maps for thousands of inner and outer hair cells of the organ of Corti, which is the first Aim of this grant application. It is anticipated that these maps, based on single cell RNA-Seq data will miss little information when compared for example with other sensory systems such as the retina, where analysis of a few thousand photoreceptor cells would represent <0.05% of the sensory cell population. It is anticipated that the maps will reveal how gradients of gene expression contribute to functional tonotopy in inner and outer hair cells. Moreover, the generated maps will serve as base line for identifying distinct changes in cochlear hair cells after noise-induced temporary threshold shift. Here, it is anticipated that the analysis will reveal functional modules of co-regulated hair bundle genes as well as candidate gene regulatory networks for susceptibility to noise-induced hearing loss. A second series of experiments aims to identify the molecular mechanisms by which non-traumatic sound exposure temporarily reduces susceptibility for permanent noise induced threshold shift. This research has the potential of elucidating genes and mechanisms involved in susceptibility to noise. Finally, it is proposed to investigate at the molecular level compensatory changes in inner and outer hair cells in response to sustained changes in cochlear integration such as lack of functional afferent or efferent innervation or lack of connection between outer hair cells and the tectorial membrane. Beside identification of co-regulated gene groups for example involved in cochlear amplification, it is expected that this research will reveal how hair cells are affected by pathological situations that do not trigger immediate hair cell loss.

Public Health Relevance

Cochlear hair cells display capacity for self-repair after noise damage and are capable of lowering susceptibility to noise damage when pre-exposed to non-traumatic sound. Likewise, hair cells respond to pathological changes in the cochlea and auditory system with compensatory mechanisms. The proposed research uses measurements of global changes in gene expression in individual mouse cochlear hair cells to discover genetic mechanisms involved in self-repair, noise susceptibility, as well as how hair cells respond to lack of functional innervation and loss of integration into the cochlear infrastructure. Besides the identification of specific genetic mechanisms, it is expected that this research will provide insight into the molecular basis of disease progression which could guide the development of intervention strategies.

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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Stanford University
Schools of Medicine
United States
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Ellwanger, Daniel C; Scheibinger, Mirko; Dumont, Rachel A et al. (2018) Transcriptional Dynamics of Hair-Bundle Morphogenesis Revealed with CellTrails. Cell Rep 23:2901-2914.e14
Hartman, Byron H; B?scke, Robert; Ellwanger, Daniel C et al. (2018) Fbxo2VHC mouse and embryonic stem cell reporter lines delineate in vitro-generated inner ear sensory epithelia cells and enable otic lineage selection and Cre-recombination. Dev Biol 443:64-77