Cell survival and cell death in the auditory nerve

听神经中的细胞存活和细胞死亡

基本信息

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
项目类别：
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

项目摘要

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 (SGN) 是主要传入神经元，携带来自听觉神经的听觉信息。耳蜗内毛细胞 (IHC) 至中枢神经系统。尽管 SGN 的退化是已知是随着损伤和年龄的增长而发生的，但人们对细胞或分子的序列知之甚少。体内发生这种病理学的事件。核因子 - KB (NF KB) 是一种已知的转录因子调节细胞凋亡以响应包括神经元在内的许多细胞类型的损伤。 NF KB 也相关细胞内Ca2+调节的功能障碍是神经元兴奋性毒性和神经元兴奋性毒性的重要因素细胞凋亡。该项目的目标是确定 NF KB 在急性急性肾损伤后 SGN 存活中的作用侮辱。野生型和 NF KB 敲除小鼠将用作动物模型。这些基因敲除小鼠表现出随着年龄的增长，进行性听力损失与 SGN 的加速退化密切相关。此外，该敲除中 SGN 放射状树突的病理学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 免于急性损伤后退化方面发挥抗凋亡作用，并且这种保护的根本机制是 NF KB 活性有助于维持 SGN 中的 Ca2+ 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 KB 的激活是否可以保护 SGN 免于响应急性噪音而退化和哇巴因暴露。噪声和哇巴因暴露允许对过程进行不同的评估 SGN 变性背后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 Ca2+ 稳态。这些实验采用电生理学、组织病理学和免疫荧光技术，以及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 SGN 退化机制，并将有助于开发新方法预防和治疗人类感音神经性听力损失。