Novel mechanism for sex differences in hearing loss

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Project Summary / Abstract There is growing awareness of the importance of sex differences in auditory function and disorders. Large-scale clinical studies have revealed a strong sex bias in hearing loss prevalence. While females have a lower overall prevalence of hearing loss, 8.3 million women have hearing impairment, and 1.67 million begin experiencing hearing loss during their middle age. Hearing loss in females worsens after menopause. Moreover, female hearing levels are more variable, suggesting disease conditions that affect subpopulations of females, increasing their vulnerability to certain otologic disorders. Autoimmune disorders preferentially affect women, leading to a higher prevalence of immune-related hearing impairment. Female-related hearing loss typically begins around the middle age and affects the low- and mid-frequencies essential for perceiving speech. At present, the underlying mechanisms for female hearing loss are poorly understood. The lack of understanding has prevented the development of diagnostic tools to determine the underlying causes of sex-dependent susceptibility to hearing loss. We recently identified a lectin family protein, galectin-3, in the cochlea. This β-galactoside-binding protein has been involved in various biological processes, including immune functions. It also has a vital role in inflammatory disorders. Our pilot observations have shown that galectin-3 is highly expressed in cochlear immune cells and supporting cells, both being immune-competent cells. This protein participates in cochlear inflammatory responses to age-related and noise-induced hearing loss. Our analysis revealed that targeted disruption of galectin-3-coding gene, Lgals3, increases female susceptibility to age-related cochlear degeneration. Identification of galectin-3 as an important sex-relevant immune molecule provides us with a powerful tool to investigate the role of immune-mediated activities in female auditory dysfunction. The long-term goal of our research is to determine the molecular mechanisms underlying sex differences in otologic disorders. The proposed research aims to use galectin-3 as a gateway to identify female-linked molecules and determine how these molecules interact with female hormones to affect female cochlear homeostasis and susceptibility to hearing disorders. Specifically, we will 1) determine the role of galectin-3 in maintaining auditory function and cochlear integrity, 2) determine immune mechanisms underlying the female susceptibility to galectin-3 deficiency, and 3) determine female hormonal regulation of cochlear gene expression. Our proposed study will address a clinically relevant but still understudied research topic, female hearing loss. Identifying molecules critical to female hearing has great potential for clinical translation. The knowledge gained from the proposed studies can guide future efforts to identify female essential molecules in human ears, which will aid in identifying clinically applicable biomarkers for revealing the underlying causes of female hearing loss. Ultimately, studying the biological basis of sex differences will provide the foundation for developing sex-dependent therapies for hearing loss.