Novel mechanism for sex differences in hearing loss

听力损失性别差异的新机制

• 批准号: 10659402
• 负责人: BO HUA HU
• 金额: $ 39.82万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659402
• 关键词: Affect; Alleles; Auditory; Auditory system; Autoimmune Diseases; Awareness; Binding Proteins; Biological; Biological Markers; Biological Process; Cells; Clinical; Clinical Research; Cochlea; Code; Congenic Mice; Data; Development; Disease; Ear; Female; Foundations; Frequencies; Future; Galectin 3; Gene Expression; Genes; Genetic; Goals; Gonadal Steroid Hormones; Hearing; Hearing problem; High Prevalence; Homeostasis; Hormones; Human; Immune; Immunocompetent; Inflammatory; Inflammatory Response; Knock-out; Knowledge; Lectin; Link; Macrophage; Mediating; Molecular; Mouse Strains; Mutation; Noise-Induced Hearing Loss; Otology; Pathogenesis; Pilot Projects; Postmenopause; Predisposition; Presbycusis; Prevalence; Production; Protein Family; Proteins; Public Health; Research; Role; Sex Bias; Sex Chromosomes; Sex Differences; Speech; Stress; Supporting Cell; Testing; Therapeutic; Woman; age related; beta-galactoside; clinical application; clinical translation; clinically relevant; diagnostic tool; experience; experimental study; hearing impairment; hearing loss treatment; hormone regulation; immune activation; immune function; immunoregulation; inner ear diseases; male; middle age; novel; prevent; response; sex; tool; trait

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.

项目总结/摘要 人们越来越意识到听觉功能和障碍的性别差异的重要性。大规模 临床研究表明，听力损失的患病率存在很大的性别偏见。而女性的整体水平较低， 听力损失的患病率，830万妇女有听力障碍，167万开始经历 中年时的听力损失绝经后女性听力损失的研究。此外，女性 听力水平变化更大，表明影响女性亚群的疾病状况， 他们对某些耳科疾病的脆弱性。自身免疫性疾病优先影响女性，导致 与免疫相关的听力障碍患病率较高。女性相关的听力损失通常始于 中年，并影响对感知语音至关重要的低频和中频。目前该 女性听力损失的潜在机制知之甚少。由于缺乏了解， 开发诊断工具，以确定性别依赖性易感性的根本原因， 听力损失我们最近在耳蜗中发现了一种凝集素家族蛋白，galectin-3。这种β-半乳糖苷结合 蛋白质参与各种生物过程，包括免疫功能。它还在以下方面发挥着至关重要的作用： 炎症性疾病我们的初步观察表明，半乳糖凝集素-3在耳蜗中高度表达， 免疫细胞和支持细胞，两者都是免疫活性细胞。这种蛋白质参与耳蜗 炎症反应与年龄相关的和噪声引起的听力损失。我们的分析显示， 半乳糖凝集素-3编码基因Lgals 3的破坏增加了女性对年龄相关性耳蜗损害的易感性 退化半乳糖凝集素-3作为一种重要的性别相关免疫分子的鉴定为我们提供了一个 研究免疫介导的活动在女性听觉功能障碍中的作用的有力工具。长期 我们的研究目标是确定耳科疾病性别差异的分子机制。 这项拟议中的研究旨在利用半乳糖凝集素-3作为识别女性连锁分子的途径， 这些分子如何与女性激素相互作用，以影响女性耳蜗的稳态和对 听力障碍具体来说，我们将1）确定半乳糖凝集素-3在维持听觉功能中的作用， 耳蜗完整性，2）确定女性对半乳糖凝集素-3易感性的免疫机制 缺乏，和3）确定耳蜗基因表达的女性激素调节。我们建议的研究将 解决了一个临床相关但仍未充分研究的研究课题，女性听力损失。识别分子 对女性听力至关重要，具有很大的临床转化潜力。从建议中获得的知识 研究可以指导未来的努力，以确定人类耳朵中的女性必需分子，这将有助于识别 用于揭示女性听力损失的根本原因的临床上适用的生物标志物。最终，学习 性别差异的生物学基础将为开发性别依赖疗法提供基础， 听力损失