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.

以前的研究表明，爆炸暴露和创伤性脑损伤（TBI）退伍军人听力正常 阈值，但表现出听觉突触病，包括中枢听觉处理缺陷和亚临床 听力障碍的程度。在外周听觉系统中，耳蜗突触病是指 内毛细胞突触在几乎正常的听力测量和毛细胞的存在下， 在年龄相关的和噪声引起的听力损失啮齿动物模型中有报道。中枢听觉知识 然而，突触病仍然非常有限。目前，中枢听觉神经系统的关键分子机制 突触病尚未确定，这限制了对中枢听觉突触病的理解， 制定具体的治疗方法。因此，对中枢听觉的研究是非常必要的 突触和突触病。在这个提议中，螺旋神经节神经元-耳蜗核（SGN-CN）突触将被 SGN-CN突触是第一个从内耳接收信号的中枢听觉中继。 如果没有功能性SGN-CN突触，听觉信号就不能有效地传递到大脑。的 本计划的目标是了解SGN-CN突触完整性的关键分子机制 并开发新的治疗方法来治疗SGN-CN突触病。颗粒蛋白前体是一种分泌型糖蛋白 它与多种神经元活动有关，包括神经元存活、神经突生长、突触形成、 形成、神经炎症和神经变性。颗粒蛋白前体在听觉突触中的作用还没有 被举报。我们的初步数据表明颗粒蛋白前体和SGN-CN突触之间的关系。 基于以前的研究和我们的初步研究，我们推测颗粒蛋白前体可能调节小鼠SGN-CN 突触完整性为了检验这一假设，我们将在Grn-/-小鼠模型中描述SGN-CN突触病的特征。 并确定颗粒蛋白前体在年轻成年小鼠SGN-CN突触完整性中发挥作用的程度 (Aim 1）。在目标2中，我们将确定颗粒蛋白前体在多大程度上拯救了SCN-1的结构和功能。 CN突触病。这一建议的结果将大大推进知识的完整性和 听觉突触的再生，这是一个在很大程度上研究不足的VA康复研究领域。如果耳蜗 在这个提议中，我们将进一步描述Grn在耳蜗中的作用。 突触病，并确定Grn-/-小鼠SGN-CN突触病是原发性，继发性，还是混合在我们的研究中。 未来的建议。此外，我们还将研究Grn在年龄相关和噪声诱导的听觉损伤中的作用。 突触病这些研究的结果将揭示听觉突触病的分子机制 并开辟了新的途径，以开发治疗听觉突触病的具体策略。