Sex Effects for Hearing Loss Drug Therapies

性对听力损失药物治疗的影响

• 批准号: 10791076
• 负责人: Parveen Bazard
• 金额: $ 41.25万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10791076
• 关键词: Acceleration; Affect; Aftercare; Age; Aging; Amino Acids; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptotic; Auditory; Auditory Brainstem Responses; Auditory system; Binaural; Biological Assay; Biological Markers; Body part; CBA/CaJ Mouse; Cells; Cellular Assay; Chemicals; Chronic; Clinic; Clinical Trials; Cochlea; Communities; Control Groups; DNA Damage; Data; Deterioration; Development; Distress; Dose; Ear; Effectiveness; Elderly; Equilibrium; Estrogens; Estrus; FDA approved; Family; Female; Free Radical Scavengers; Future; Gene Expression; Genes; Genetic; Glutathione; Gonadal Steroid Hormones; Grant; Hair Cells; Half-Life; Health; Hearing; Hormones; Human; Human body; Immunohistochemistry; Inflammation; Inner Hair Cells; Intervention; Knock-out; Loneliness; Longitudinal Studies; Mammals; Medical; Menopause; Mental Depression; Mitochondria; Mitochondrial DNA; Modeling; Molecular Biology; Mus; Nerve Degeneration; Neurodegenerative Disorders; No-Observed-Adverse-Effect Level; Noise; Operative Surgical Procedures; Ovariectomy; Ovary; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathway interactions; Perimenopause; Periodicity; Peripheral; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Pilot Projects; Plasma; Postmenopause; Premenopause; Presbycusis; Primordial Follicle; Production; Progesterone; Progestins; Property; Proteomics; Reaction; Regulation; Reporting; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; SOD2 gene; Safety; Saline; Sensorineural Hearing Loss; Sensory; Sensory Disorders; Sex Differences; Speech; Speech Perception; Stria Vascularis; Structure; Sulfhydryl Compounds; TNF gene; Techniques; Testing; Therapeutic; Thiones; Time; Tinnitus; Tissues; United States National Institutes of Health; Western Blotting; absorption; aging auditory system; aging population; body system; cell injury; chelation; clinically significant; comorbidity; comparative efficacy; dementia risk; dietary; divalent metal; experience; fascinate; hearing impairment; hearing measurement; improved; inflammatory marker; inflammatory modulation; innovation; intraperitoneal; male; middle age; molecular marker; mouse model; novel; otoacoustic emission; ovarian failure; pre-clinical; preclinical study; preservation; prevent; prospective; protective effect; receptor; receptor expression; sex; side effect; social implication; spiral ganglion; success; tautomer; uptake; young adult

Age-related hearing loss (ARHL), also known as presbycusis, is the predominant sensory disorder and neurodegenerative condition of our aged population. Like many other body systems, hearing and its associated structures decline with age, with most people experiencing some form of hearing loss by the age 60. ARHL is gradual deterioration of auditory sensitivity, speech perception and binaural processing with age. There are both health and social implications associated with ARHL as it has been related to other health problems, such as an increased risk for dementia, depression, distress, and loneliness. It also decreases ability of our elderly to live independently and increases their reliance on family and/or community support. There is no way to prevent or reverse ARHL, and currently, there is no FDA-approved drugs to prevent or treat sensorineural hearing loss. Most pre-clinical studies carried out so far have targeted one pathway. Here, I propose to investigate a therapy that can target various pathways simultaneously. Specifically, the therapeutic potential of L-ergothioneine will be investigated. Ergothioneine is a naturally occurring “super-antioxidant/anti- inflammatory” that has intrigued many researchers since the discovery of its specific receptor OCTN1 in the human body in 2005. It accumulates in various parts of the body depending upon its receptor expression levels. It exists in tautomer equilibrium (thiol and thione forms), with the thione form favored at physiological pH. Furthermore, its high redox potential (-0.06 V vs -0.2 to -0.32 V for other antioxidant thiols like glutathione) and high safety profile (NAOEL = 800 mg/kg/day) makes it a stable and effective antioxidant. We anticipate that it will also help in mitigating some of the key aspects of age-related hearing loss as well, since it is also an anti-apoptotic. We have produced some exciting preliminary results – protective effects on auditory brainstem response thresholds and on distortion product otoacoustic emission thresholds & amplitudes for aging CBA/CaJ male mice (~25 months old, 6-month longitudinal study) but not for females These preliminary results are novel and groundbreaking as no previous reports are available about EGT beneficial effects on the aging auditory system. In the present proposal, we will further develop the treatment paradigm of EGT in females by applying EGT therapies at different time points (pre, peri and post-menopausal) during the menopause transition with the hypothesis that there is a “golden-window” during this phase where ergothioneine will be beneficial for the females. This grant will help us to generate more initial results for pre- clinical treatment paradigms of ergothioneine to treat hearing loss. Note that EGT has a very safe and is readily available for human use, hence, if successful, our new findings will be rapidly translatable to the clinic.

听觉相关性听力损失（ARHL），也称为老年性耳聋，是主要的感觉障碍， 我们老年人的神经退行性疾病。像许多其他身体系统一样，听觉及其相关的 随着年龄的增长，听力结构会下降，大多数人在60岁时都会出现某种形式的听力损失。ARHL是 随着年龄的增长，听觉灵敏度、言语感知和双耳处理逐渐退化。有 与ARHL相关的健康和社会影响，因为它与其他健康问题有关，例如 痴呆症、抑郁症、痛苦和孤独的风险增加。它也降低了我们老年人的能力 独立生活，增加对家庭和/或社区支持的依赖。没有办法 预防或逆转ARHL，目前还没有FDA批准的药物来预防或治疗感觉神经性 听力损失迄今为止，大多数临床前研究都针对一种途径。在此，我提议 研究一种可以同时针对多种途径的疗法。具体而言， 将研究L-麦角硫因。麦角硫因是一种天然存在的“超级抗氧化剂/抗- 自从在肿瘤组织中发现其特异性受体OCTN 1以来， 2005年人体依赖于受体的表达，它在身体的各个部位积累 程度.它存在于互变异构体平衡中（硫醇和硫醇形式），其中硫醇形式在生理上是有利的。 博士此外，其高氧化还原电位（-0.06 V vs-0.2至-0.32 V的其他抗氧化剂硫醇，如谷胱甘肽） 高安全性（NAOEL = 800 mg/kg/天）使其成为稳定有效的抗氧化剂。我们预计 它也将有助于减轻与年龄相关的听力损失的一些关键方面，因为它也是一种 抗凋亡的。我们已经产生了一些令人兴奋的初步结果-对听觉脑干的保护作用 老化的响应阈值和畸变产物耳声发射阈值和振幅 CBA/CaJ雄性小鼠（~25月龄，6个月纵向研究），但雌性小鼠不存在。 结果是新颖的和突破性的，因为以前没有关于EGT对 老化的听觉系统在目前的建议中，我们将进一步发展EGT的治疗模式， 在绝经期间的不同时间点（绝经前、绝经后和绝经后）应用EGT治疗， 更年期过渡的假设，有一个“黄金窗口”在这个阶段， 麦角硫因对女性有益。这笔赠款将帮助我们产生更多的初步成果， 麦角硫因治疗听力损失的临床治疗范例。请注意，EGT具有非常安全的 因此，如果成功的话，我们的新发现将迅速转化为临床。