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: 7178505
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7178505
• 关键词: Cell; survival; cell; death; auditory

DESCRIPTION (provided by applicant): 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 NF KB 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 NF KB activity is required to maintain Ca2+ homeostasis in SGNs after these acute insults. These experiments employ electrophysiological, histopathological and immunofluorescence 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.

描述（由申请人提供）：螺旋神经节神经元（SGN）是主要传入神经元，可从耳蜗内部毛细胞（IHC）传递听觉信息到中枢神经系统。尽管已知SGN的变性是响应损伤而发生的，并且随着年龄的增长，对这种病理学的细胞或分子事件的序列鲜为人知。核因子-Kb（NF KB）是一种转录因子，已知可以根据包括神经元在内的许多细胞类型的侮辱来调节凋亡。 NF KB还与细胞内Ca2+调节有关，其功能障碍是神经元兴奋性和凋亡的重要因素。该项目的目的是确定NF KB在急性侮辱后SGN生存中的作用。野生型和NF KB敲除小鼠将用作动物模型。这些敲除小鼠显示出随着年龄的增长而进行的逐渐听力损失，这与SGNS的加速变性密切相关。此外，在此敲除中SGN径向树突的病理表明，IHC突触的传入树突中存在过度的兴奋性毒性。基于这些观察结果，我们假设NF KB在保护SGN免受急性损伤后免受变性中起抗凋亡作用，并且这种保护的基本机制是NF KB活性有助于维持SGN中的Ca2+稳态以减少兴奋性毒性作用。这些假设将以两个特定的目的进行检验。第一个目的将确定NF KB在体内的激活是否会响应急性噪声和OUABAIN暴露而保护SGN免受变性。噪声和Ouabain暴露允许对兴奋性毒性和凋亡过程中SGN变性的过程的不同评估。第二个目标将确定在这些急性侮辱后是否需要NF KB活动以维持SGN中的Ca2+稳态。这些实验采用电生理，组织病理学和免疫荧光技术，以及使用电泳迁移率转移测定法（EMSA）和实时逆转录聚合酶链（RT-PCR）的实验。这些研究的结果将使人们对SGN变性的细胞和分子机制有更好的了解，并有助于开发新的方法来预防和治疗人类的感觉性听力损失。