Regeneration of Auditory Synapses

听觉突触的再生

• 批准号: 10701293
• 负责人: Zhengqing Hu
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701293
• 关键词: AD transgenic mice; Age; Area; Atrophic; Auditory; Auditory Brainstem Responses; Auditory Threshold; Auditory system; Biological Assay; Brain; Central Nervous System; Cochlear Implants; Cochlear nucleus; Coculture Techniques; Data; Defect; Development; Environment; Exhibits; Functional Regeneration; Future; GRN gene; Glycoproteins; Green Fluorescent Proteins; Hair Cells; Hearing; Hearing problem; Homozygote; Impairment; In Vitro; Inflammation; Injury; Inner Hair Cells; Knockout Mice; Knowledge; Labyrinth; Measurement; Messenger RNA; Methods; Molecular; Mouse Protein; Mus; Natural regeneration; Nerve Degeneration; Neurites; Neurons; Noise; Noise-Induced Hearing Loss; Outcome; Outcome Study; PGRN gene; Patients; Peripheral; Peripheral Nervous System; Pilot Projects; Presbycusis; Reporting; Research; Rodent Model; Role; Series; Signal Transduction; Structure; Synapses; Synaptic Vesicles; Testing; Therapeutic; Traumatic Brain Injury; Veterans; age related; auditory pathway; auditory processing; blast exposure; cell injury; clinical application; cochlear synaptopathy; congenic; density; enhanced green fluorescent protein; hearing impairment; improved; in vivo; mouse model; neural; neuroinflammation; neuronal survival; normal hearing; novel therapeutic intervention; postnatal; rehabilitation research; restoration; speech recognition; spiral ganglion; success; synaptogenesis; treatment strategy; young adult

Previous studies showed that blast-exposed and traumatic brain injury (TBI) Veterans had normal hearing thresholds but exhibited auditory synaptopathy, including central auditory processing deficits and subclinical levels of hearing dysfunction. In the peripheral auditory system, cochlear synaptopathy is the degeneration of inner hair cell synapses in the presence of nearly normal audiometric measurements and hair cells, which has been reported in age-related and noise-induced hearing loss rodent models. Knowledge of central auditory synaptopathy, however, remains very limited. Currently, the molecular mechanism critical for central auditory synaptopathy has not been determined, which restricts the understanding of central auditory synaptopathy and the development of specific treatment methods. Therefore, there is a critical need to study central auditory synapse and synaptopathy. In this proposal, spiral ganglion neuron-cochlear nucleus (SGN-CN) synapse will be investigated, as the SGN-CN synapse is the first central auditory relay that receives signals from the inner ear. Without functional SGN-CN synapses, auditory signals cannot be efficiently transferred to the brain. The objectives of this proposal are to understand the molecular mechanism critical for SGN-CN synapse integrity and develop novel therapeutic approaches to treat SGN-CN synaptopathy. Progranulin is a secreted glycoprotein that is associated with a variety of neuronal activities, including neuronal survival, neurite outgrowth, synapse formation, neuroinflammation, and neurodegeneration. The role of Progranulin in auditory synapses has not been reported. Our preliminary data suggest the relationship between Progranulin and SGN-CN synapses. Based on previous and our preliminary data, we hypothesize that Progranulin may regulate mouse SGN-CN synapse integrity. To test this hypothesis, we will characterize SGN-CN synaptopathy in the Grn-/- mouse model and determine the extent to which Progranulin plays a role in young adult mouse SGN-CN synapse integrity (Aim 1). In Aim 2, we will determine the extent to which Progranulin rescues the structure and function of SCN- CN synaptopathy. The results of this proposal will significantly advance knowledge in the integrity and regeneration of auditory synapses, which is a largely understudied VA rehabilitation research area. If cochlear synaptopathy is found in the Grn-/- mouse in this proposal, we will further characterize the role of Grn in cochlear synaptopathy and determine whether Grn-/- mouse SGN-CN synaptopathy is primary, secondary, or mixed in our future proposals. Additionally, we will investigate the role of Grn in age-related and noise-induced auditory synaptopathy. Outcome of these studies will unravel the molecular mechanisms critical for auditory synaptopathy and open new avenues to develop specific strategies for the treatment of auditory synaptopathy.

先前的研究表明，暴露于爆炸和创伤性脑损伤（TBI）的退伍军人听力正常 阈值但表现出听觉突触病，包括中央听觉处理缺陷和亚临床 听力功能障碍的水平。在外围听觉系统中，人工耳蜗突触病是 内毛细胞在存在几乎正常的听力测量和毛细胞的情况下突触 报道了与年龄相关的和噪声引起的听力损失啮齿动物模型的报道。中央听觉知识 但是，突触病仍然非常有限。目前，中央听觉至关重要的分子机制 尚未确定突触病，这限制了中央听觉突触病和 特定治疗方法的发展。因此，迫切需要研究中央听觉 突触和突触病。在此提案中，螺旋神经节神经元 - 螺旋核（SGN-CN）突触将是 研究了，因为SGN-CN突触是第一个从内耳接收信号的中央听觉继电器。 没有功能性SGN-CN突触，听觉信号将无法有效地转移到大脑中。这 该建议的目标是了解SGN-CN突触完整性至关重要的分子机制 并开发新的治疗方法来治疗SGN-CN突触病。尿素是一种分泌的糖蛋白 这与各种神经元活动有关，包括神经元存活，神经突生长，突触 形成，神经炎症和神经变性。前素蛋白在听觉突触中的作用尚未 报道了。我们的初步数据表明，progranulin和SGN-CN突触之间的关系。 根据以前的和我们的初步数据，我们假设progranulin可能调节小鼠SGN-CN 突触完整性。为了检验该假设，我们将表征GRN - / - 鼠标模型中的SGN-CN突触病 并确定在年轻的成年小鼠SGN-CN突触完整性中易作用的程度 （目标1）。在AIM 2中，我们将确定促素蛋白在多大程度上挽救SCN-的结构和功能 CN突触病。该提案的结果将大大提高对完整性的知识和 听觉突触的再生，这是一个在很大程度上研究的VA康复研究领域。如果人工耳蜗 突触病在该提案中的GRN - / - 小鼠中发现，我们将进一步表征GRN在人耳蜗中的作用 突触病，并确定GRN - / - 小鼠SGN-CN突触病是主要的，次要的还是在我们的 未来的建议。此外，我们将研究GRN在与年龄相关的和噪声引起的听觉中的作用 突触病。这些研究的结果将揭示对听觉突触病至关重要的分子机制 并开放新的途径，以制定治疗听觉突触病的特定策略。