Molecular and Functional Mechanisms of the Aging Auditory Neuron

摘要： 我们试图了解年龄相关听力的神经细胞、功能和分子机制。 损失(ARHL)。这个独立而又莫名其妙地交织在一起的提案是建立在最初令人信服的 发展和发现。与早先的报道不同，我们意外地发现了潜在的神经元退化 传入螺旋神经节神经元(SGN)-毛细胞(HC)突触在任何明显的外周表现之前 毛细胞(HC)束断裂和HC丢失，使用公认的和独特的ARHL小鼠模型。鼠标 LINE具有类似于人类衰老的听力特征。我们还在功能上演示了 老化的SGN经历了膜输入阻力的逐步减少，导致切除能力降低。 受这些令人兴奋的发现的启发，我们假设“无声神经元和突触变性”可能是 缓解急性淋巴细胞性白血病的首要目标。 我们建议确定ARHL的生理神经机制，并与 项目(P)1和3以及核心B-C(在项目总主题中概述)，确定候选基因 参与并展示抗击该疾病的必要策略。 该提议的主要假设是老化的感觉上皮细胞经历结构变化。 这使得高K+内淋巴渗入外淋巴，触发感觉细胞(HC和SGN) 去极化，细胞内钙离子([Ca+]i)增加以及随后的“潜伏”突触和神经元 退化。我们进一步假设结构变化是通过减弱紧密连接(TJ)来实现的。 在老化的感觉上皮细胞中。Claudin 9和occludin是耳蜗感觉中的TJ蛋白 并将被用作原型来检验我们的假设。 携带cldn9、Ocln、强力霉素和光介导基因之一的遗传性小鼠模型 来检验这些假说的操纵。拟议的研究将揭示ARHL的关键神经机制。 结合来自P1和3以及B-C核心的数据，新的治疗靶点用于治疗 将对ARHL进行评估、测试和建议。这一结果可能会改变和改变盛行的 从描述性到机械性和翻译性平台的范例。

Abstract: We seek to understand the neuro-cellular, functional, and molecular mechanisms of age-related hearing loss (ARHL). This independent, yet inexplicably intertwined proposal is predicated on the initial compelling development and findings. In contrast to earlier reports, we found to our surprise latent neuronal degeneration of afferent spiral ganglion neuron (SGN)-hair cell (HC) synapses prior to any apparent manifestation of outer hair cell (HC) bundle disruption and HC loss, using a recognized and distinct ARHL mouse model. The mouse line has hearing characteristics similar to humans aging. We have also demonstrated functionally that the aging SGNs undergo step-wise reduction in membrane input resistance leading to reduced excitibility. Motivated by these exciting findings, we hypothesize that “silent neuronal and synaptic degeneration” may be the preeminent target to alleviate ARHL. We propose to determine the physiological neural mechanisms of ARHL and in close collaboration with Projects (P) 1 and 3 and Cores B-C (outlined in the overal theme of the project), identify candidate genes involved and demonstrate strategies necessary to counter the disease. The overarching hypothesis of the proposal is that the aging sensory epithelia undergo structural changes that allow the high K+ endolymph to leak into the perilymph, triggering sensory-cell (HC and SGN) depolarization, increased intracellular Ca2+ ([Ca2+]i) and subsequent “latent” synaptic and neuronal degeneration. We further hypothesize that structural changes are mediated by weakening tight junctions (TJs) in the aging sensory epithelia. Claudin 9 and Occludin are identified TJ proteins in the cochlear sensory epithelium and will be used as a prototype to test our hypotheses. Genetic mouse models carrying one allele of Cldn 9 and Ocln and doxycycline and light-mediated gene manipulations to test these hypotheses. The proposed studies will reveal critical neural mechanisms of ARHL and together with data derived from P1 and 3 and Cores B-C, new therapeutic targets for the treatment of ARHL will be assessed, tested and proposed. The results are likely to transform and shift the prevailing paradigm from descriptive to mechanistic and translational platforms.