Cell survival and cell death in the auditory nerve

螺旋神经节神经元（SGN）是初级传入神经元，其携带来自耳蜗的听觉信息。 耳蜗的内毛细胞（IHC）对中枢神经系统的影响。虽然SGN的退化是 已知发生在响应损伤和随着年龄的增长，很少有人知道的细胞或分子的序列， 在体内引起这种病理学的事件。核因子- KB（NF-KB）是已知的转录因子， 调节包括神经元在内的许多细胞类型对损伤的凋亡反应。NF KB也与 与细胞内Ca 2+调节，其功能障碍是神经元兴奋性毒性的重要因素， 凋亡本项目的目的是确定NF-κ B在急性胰腺炎后SGN存活中的作用。 侮辱。将野生型和NF κ B敲除小鼠用作动物模型。这些基因敲除小鼠表现出 随着年龄的增长而进行性听力损失与SGN的加速退化密切相关。 此外，SGN放射状树突在这种敲除的病理学表明，过度的兴奋毒性是 存在于IHC突触处的传入树突中。基于这些观察，我们假设NF κ B 在保护SGN免于急性损伤后的变性中起抗凋亡作用， 这种保护的潜在机制是NF κ B活性有助于维持SGN中的Ca 2+稳态， 减少兴奋性毒性作用。这些假设将通过两个具体目标进行检验。第一个目标将 确定体内NF-κ B的激活是否保护SGN免受急性噪声的降解 和哇巴因暴露。噪声和哇巴因暴露允许对以下过程进行不同的评估： SGN变性的兴奋性毒性和细胞凋亡。第二个目标将决定NFKB是否 在这些急性损伤后，需要活性来维持SGN中的Ca 2+稳态。这些实验 采用电生理学、组织病理学和免疫荧光技术，沿着那些使用 电泳迁移率变动分析（EMSA）和实时逆转录聚合酶链反应 （RT-PCR）。这些研究的结果将有助于更好地了解细胞和分子生物学。 SGN变性的机制，并将有助于开发新的方法， 预防和治疗人类感觉神经性听力损失。

Spiral ganglion neurons (SGNs) are the primary afferent neurons that carry auditory information from the inner hair cells (IHCs) of the cochlea to the central nervous system. Although degeneration of SGNs is known to occur in response to injury and with age, little is known about the sequence of cellular or molecular events underlying this pathology in vivo. Nuclear factor - KB (NF KB) is a transcription factor that is known to regulate apoptosis in response to insults in many cell types, including neurons. NF KB is also associated with intracellular Ca2+ regulation, the dysfunction of which is an important factor in neuronal excitotoxicity and apoptosis. The goal of this project is to determine the role of NF KB in the survival of SGNs following acute insults. Wild type and NF KB knockout mice will be used as animal models. These knockout mice show a progressive hearing loss with age that is closely correlated with accelerated degeneration of SGNs. Moreover, the pathology of the SGN radial dendrites in this knockout suggests that excessive excitotoxicity is present in the afferent dendrites at IHC synapses. Based on these observations, we hypothesize that NFKB plays an anti-apoptotic role in the protection of SGNs from degeneration after acute injury, and that the underlying mechanism of this protection is that NF KB activity helps maintain Ca2+ homeostasis in SGNs to reduce excitotoxic effects. These hypotheses will be tested with two specific aims. The first aim will determine whether activation of NF KB in vivo protects SGNs from degeneration in response to acute noise and ouabain exposures. The noise and ouabain exposures allow differing assessments of the processes of excitotoxicity and apoptosis underlying SGN degeneration. The second aim will determine whether NFKB activity is required to maintain Ca2+ homeostasis in SGNs after these acute insults. These experiments employ electrophysiological, histopathological and immunoflourescence techniques, along with those using electrophoretic mobility shift assay (EMSA) and real-time reverse transcription polymerase chain reaction (RT-PCR). The results of these studies will lead to a better understanding of the cellular and molecular mechanisms of SGN degeneration and will contribute to the development of novel approaches to the prevention and treatment of sensorineural hearing loss in humans.