Regeneration of Auditory Synapses

先前的研究表明，爆炸暴露和创伤性脑损伤(TBI)退伍军人的听力正常 阈值，但表现为听觉突触，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，耳蜗性突触是一种退行性病变 在几乎正常的听力测量和毛细胞存在的情况下，内毛细胞突触，这有 在年龄相关和噪声诱导的听力损失啮齿动物模型中已有报道。中枢性听觉知识 然而，突触作用仍然非常有限。目前，中枢听觉的关键分子机制 突触作用尚未确定，这限制了对中枢性听觉性突触和 制定具体的治疗方法。因此，迫切需要对中枢听觉进行研究。 突触和突触。在这项提议中，螺旋神经节神经元-耳蜗核(SGN-CN)突触将 研究发现，SGN-CN突触是第一个从内耳接收信号的中枢听觉中继器。 如果没有功能正常的SGN-CN突触，听觉信号就不能有效地传输到大脑。这个 这项建议的目的是了解对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。原颗粒蛋白是一种分泌型糖蛋白 这与多种神经元活动有关，包括神经元存活、轴突生长、突触 形成、神经炎症和神经退行性变。原颗粒在听觉突触中的作用尚未见报道 已经上报了。我们的初步数据提示前颗粒蛋白与SGN-CN突触之间的关系。 根据前人和我们的初步数据，我们假设原颗粒可能调节小鼠SGN-CN 突触的完整性。为了验证这一假设，我们将在Grn-/-小鼠模型中描述SGN-CN突触的特征 并确定原颗粒在幼年小鼠SGN-CN突触完整性中的作用程度 (目标1)。在目标2，我们将确定原颗粒在多大程度上挽救SCN的结构和功能- CN突触。这项提议的结果将极大地促进对廉正和 听觉突触的再生，这在很大程度上是一个未被研究的VA康复研究领域。如果是人工耳蜗 在Grn-/-小鼠中发现了突触。在这项建议中，我们将进一步描述Grn在耳蜗中的作用 突触和确定Grn-/-小鼠SGN-CN突触是主要的、继发性的还是混合的 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中的作用 突触疗法。这些研究的结果将揭开听觉突触的关键分子机制 并开辟新的途径，开发治疗听觉性突触的具体策略。

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.