Cell survival and cell death in the auditory nerve

听神经中的细胞存活和细胞死亡

• 批准号: 7352782
• 负责人: Hainan Lang
• 金额: $ 7.09万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7352782
• 关键词: Acoustic Nerve; Action Potentials; Acute; Afferent Neurons; Age; Animal Model; Animals; Apoptosis; Apoptotic; Appendix; Auditory; Brain Ischemia; Cell Count; Cell Death; Cell Survival; Cessation of life; Chromosome Pairing; Cochlea; Cochlear Implants; Data; Dendrites; Development; Electrons; Electrophoretic Mobility Shift Assay; Equilibrium; Event; Excitotoxic lesion; Functional disorder; Genes; Genotype; Goals; Hair Cells; Homeostasis; Hour; Human; Injury; Inner Hair Cells; Knock-out; Knockout Mice; Lateral; Lead; Lesion; Light; Measures; Microscopic; Modeling; Molecular; Monitor; Mus; NF-kappa B; Nerve Degeneration; Neuraxis; Neurons; Noise; Noise-Induced Hearing Loss; Nuclear; Ouabain; Outer Hair Cells; Output; Pathology; Peripheral; Pharmaceutical Preparations; Physiological; Play; Polymerase Chain Reaction; Prevention approach; Process; Process Assessment; Proteins; Publications; Radial; Regulation; Reverse Transcription; Role; Sensorineural Hearing Loss; Structure; Synapses; TNFRSF5 gene; Techniques; Testing; Text; Time; Tissues; base; cell type; excitotoxicity; hearing impairment; in vivo; neuronal cell body; novel strategies; otoacoustic emission; relating to nervous system; research study; response; response to injury; round window; spiral ganglion; success; transcription factor

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.

螺旋神经节神经元是传递听觉信息的初级传入神经元。 耳蜗内毛细胞(IHC)至中枢神经系统。虽然神经节细胞的退化是 已知发生在对损伤的反应中，并且随着年龄的增长，对细胞或分子的序列知之甚少 活体内这种病理的基础事件。核因子-KB(NFKB)是一种已知的转录因子 调节包括神经元在内的许多细胞类型对侮辱的反应中的细胞凋亡。还关联了NFKB 具有细胞内钙调节功能，其功能障碍是神经元兴奋性毒性和 细胞凋亡。本项目的目标是确定核因子kB在急性脑缺血后SGN存活中的作用。 侮辱。将野生型和NFKB基因敲除小鼠作为动物模型。这些基因敲除的老鼠显示出 进行性听力损失随年龄增长，与神经节细胞加速变性密切相关。 此外，在这种敲除中SGN放射状树突的病理表明，过度的兴奋毒性是 存在于IHC突触的传入树突中。基于这些观察，我们假设NFKB 在保护SGN急性损伤后不变性方面起到抗细胞凋亡的作用，并且 这种保护的潜在机制是，核因子KB活性有助于维持SGN内钙的动态平衡，以 减少兴奋性毒性作用。这些假说将通过两个具体目标进行检验。第一个目标是 确定体内激活核因子kB是否能保护急性噪声引起的神经节细胞免于变性 和哇巴因暴露。噪音和哇巴因暴露允许不同的评估过程 兴奋性毒性和细胞凋亡是SGN变性的基础。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中的钙稳态。这些实验 使用电生理、组织病理学和免疫荧光技术，以及那些使用 凝胶迁移率改变分析与实时逆转录聚合酶链式反应 (RT-PCR)。这些研究的结果将有助于更好地理解细胞和分子。 SGN变性的机制，并将有助于开发新的方法来治疗 人类感音神经性耳聋的防治。