Sex Effects for Hearing Loss Drug Therapies

年龄相关性听力损失(ARHL)，也被称为老年性耳聋，是主要的感觉障碍和 我国老年人口的神经退行性疾病。像许多其他身体系统一样，听力及其相关的 结构随着年龄的增长而衰退，大多数人在60岁之前会经历某种形式的听力损失。ARHL是 随着年龄的增长，听觉敏感度、言语知觉和双耳处理能力逐渐下降。确实有 与急性呼吸道合并症有关的健康和社会影响，因为它与其他健康问题有关，如 会增加患痴呆症、抑郁、痛苦和孤独的风险。它还降低了我们老年人的能力 独立生活，并增加对家庭和/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 听力损失。到目前为止，大多数临床前研究都是针对一种途径。在此，我建议 研究一种可以同时针对不同途径的治疗方法。具体地说，它的治疗潜力 L-麦角硫蛋白将被调查。麦角硫蛋白是一种天然存在的“超抗氧化剂/抗氧化剂” 自从其特异性受体OCTN1在小鼠脑内被发现以来，引起了许多研究人员的兴趣 2005年的人体。根据其受体的表达，它在身体的不同部位蓄积 级别。它存在于互变构体平衡中(硫醇和硫酮形式)，在生理上硫酮形式更受欢迎 PH值。此外，其高氧化还原电位(-0.06V对-0.2至-0.32V对于其他抗氧化剂硫醇，如谷胱甘肽) 高安全性(NAOEL=800毫克/公斤/天)使其成为一种稳定有效的抗氧化剂。我们期待着 它还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 抗凋亡剂。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 反应阈值和失真产物耳声发射阈值&老化的幅度 CBA/CAJ雄性小鼠(约25个月大，6个月纵向研究)，但不适用于雌性小鼠 结果是新颖的和开创性的，因为以前没有关于EGT对心脏的有益影响的报道 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 通过在不同的时间点(绝经前、围绝经期和绝经后)应用EGT疗法 更年期过渡的假设是在这一阶段有一个“黄金窗口”， 麦角硫氨酸将对雌性有益。这笔赠款将帮助我们为Pre-Rate生成更多的初步结果 麦角硫蛋白治疗听力损失的临床治疗方案。请注意，EGT具有非常安全的 因此，如果成功，我们的新发现将很快转化为临床。

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.