Defining the molecular mechanisms underlying sex-differences in the maintenance of hearing.

Sex impacts the maintenance of hearing over the life course. Onset, severity, and prevelance of age-related/adult-onset hearing loss (ARHL) are not equivalent in men and women, so why should we presume the genetic drivers and the molecular pathways are equivalent? Estrogen-related receptor gamma (Esrrg), a transcription factor, is the only gene identified to date which shows a sex-specific association with ARHL in women of post-menopausal age. In this proposal, I will adopt a cross-disciplinary approach encompassing auditory electrophysiological recordings and single-cell transcriptomics in genetically modified/ovariectomised mice to understand if we can use the transcriptional signature of Esrrg and/or estrogen-signaling to maintain hearing. Pilot data shows that loss of Esrrg in development leads to an auditory neuropathy. Here, I will establish if the molecular pathways regulated by Esrrg early in cochlear development are those by which Esrrg maintains hearing, and how sex impacts these pathways. Subsequently, I will determine if Esrrg and/or estogen-signaling are pivotal for cochlear synaptic and myelin health over the life course, the dysfunction of which, are both associated with early pathological changes in hearing. Finally, I will conduct proof-of-principle studies to determine if manipulating Esrrg and/or estrogen- signaling can be used to rebuild synapses/remyelinate the cochlea.