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.

项目摘要/摘要 人们越来越意识到性别差异在听觉功能和听觉障碍中的重要性。大规模 临床研究表明，听力损失的患病率存在很强的性别偏见。而女性的总体水平较低 听力损失的流行率，830万妇女听力受损，167万妇女开始出现听力障碍 在他们中年时听力丧失。女性的听力损失在绝经后会恶化。此外，女性 听力水平的变化更大，这表明影响女性亚群的疾病情况越来越多。 他们对某些耳科疾病的易感性。自身免疫性疾病优先影响女性，导致 免疫相关听力损害的患病率较高。与女性相关的听力损失通常始于 中年，并影响感知语言所必需的低、中频。目前， 女性听力损失的潜在机制还知之甚少。缺乏理解使我们无法 开发诊断工具以确定性别依赖易感性的潜在原因 听力损失。我们最近在耳蜗中发现了一个凝集素家族蛋白Galectin-3。这种β-半乳糖苷结合 蛋白质参与了包括免疫功能在内的各种生物过程。它还在以下方面发挥了重要作用 炎症性疾病。我们的初步观察表明Galectin-3在耳蜗组织中高度表达 免疫细胞和支持细胞，两者都是免疫活性细胞。该蛋白参与耳蜗肌的发育。 老年性和噪声性听力损失的炎症反应。我们的分析显示，有针对性的 Galectin-3编码基因Lgals3的缺失增加了女性对年龄相关耳蜗病的易感性 退化。Galectin-3是一种重要的性别相关免疫分子，为我们提供了一种 研究免疫调节活动在女性听力障碍中的作用的有力工具。长期的 我们研究的目的是确定耳科疾病性别差异的分子机制。 这项拟议的研究旨在利用Galectin-3作为一种途径来识别女性连接的分子并确定 这些分子如何与女性激素相互作用，影响女性耳蜗的动态平衡和易感性 听力障碍。具体地说，我们将1)确定Galectin-3在维持听觉功能和 耳蜗完整性，2)决定女性对Galectin-3易感性的免疫机制 缺乏，以及3)决定了女性激素对耳蜗基因表达的调节。我们建议的研究将 谈到一个与临床相关但仍未得到充分研究的研究主题--女性听力损失。识别分子 对女性听力至关重要的词具有很大的临床翻译潜力。从建议中获得的知识 研究可以指导未来识别人类耳朵中的女性基本分子的努力，这将有助于识别 揭示女性听力损失潜在原因的临床可用生物标志物。归根结底，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。