Treafment omcl prophylaxis of censommeural heaning loss by reguiating of transcription factor

通过调节转录因子治疗 omcl 预防耳廓听力损失

• 批准号: 13671798
• 负责人: OGAWA Kaoru
• 金额: $ 2.3万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671798/
• 关键词: sensorinenural pssaringle; frascription factor; temporary thresholol shift; activator protein-1; oxpdaftve stress; c-Fos; HIF-1; 音響外傷; C-FOS; c-FOS

Exposure to intense noise has been known to increase the reactive oxygen species (ROS) and cause an oxidative stress in the cochlea. The relationship between the ROS formation and hearing loss has been also suggested. Activator protein-1 (AP-1) is one of these transcription factors and has been known to participate in stress-induced apoptosis in neuronal death and also in survival function. AP-1 binds to the oligonucleotides with a consensus core sequence (TGAG/CTCA) at an enhancer region on DMA and modulates transcription of its inducible target. AP-1 consists of homodimer of Jun family proteins (c-Jun, Jun B, Jun D) or heterodimer of Jun and Fos family proteins (c-Fos, Fra-1 , Fra-2, Fos B) Various types of stress to neuronal cells caused by ROS, amino acid receptors such as NMDA and kainic acid receptors, seizures, and transient brain ischemia are known to induce AP-1. Recently we have shown that acoustic trauma enhanced DNA binding of AP-1 in the cochlea, and it was at least in par … More t due to the expression of c-Fos protein. In this research, noise-induced permanent threshold shift (PTS) which causes apoptotic changes in the cochlea was used as an acoustic trauma model. Because AP-1 is known to participate in both of apoptotic and survival reactions in neuronal cells, therefore, the PTS model shows two possibilities of AP-1 functions, apopttsis and survival. In this resaerch, we employed noise-induced temporary threshold shift (TTS), which is known not to include apoptotic changes in order to elucidate the contribution of AP-1 for the survival of hair cellsGuinea pigs were exposed to 4kHz band noise of 110dB SPL for 1 to 5 hrand the expression of c-Fos was proved using the Western blotting analysis and immunocytchemistry. The Westem blotting showed c-Fos expression in the organ of Corti and lateral wall including the stria vascularis, but not in the cochlear modiolus including the spiral ganglion cells. Immunocytochemistry of the organ of Corti showed c-Fos expression only after the noise exposure. The c-Fos expression was mainly found in the Hensen cells and Deiter's cells of the basal and second turns of cochlea. As the threshold shift was temporary, the expression of c-Fos is supposed to contribute for the survival or protective functions of the organ of Corti. Less

暴露于强噪声已知会增加活性氧（ROS）并引起耳蜗中的氧化应激。ROS的形成与听力损失之间的关系也被提出。激活蛋白-1（AP-1）是这些转录因子中的一种，并且已知其参与应激诱导的神经元死亡中的细胞凋亡以及存活功能。AP-1在DNA上的增强子区域与具有共有核心序列（TGAG/CTCA）的寡核苷酸结合，并调节其诱导型靶点的转录。AP-1由Jun家族蛋白的同源二聚体（c-Jun、Jun B、Jun D）或Jun和Fos家族蛋白的异源二聚体（c-Fos、Fra-1、Fra-2、Fos B）组成。已知由ROS、氨基酸受体如NMDA和红藻氨酸受体、癫痫发作和短暂脑缺血引起的对神经元细胞的各种类型的应激诱导AP-1。最近，我们发现声损伤增强了耳蜗AP-1的DNA结合，并且至少与耳蜗内AP-1的DNA结合有关。 ...更多信息 t由于c-Fos蛋白的表达。本研究以噪声诱导的永久性听阈漂移（PTS）作为声损伤模型，通过改变听阈，观察其对耳蜗细胞凋亡的影响。由于已知AP-1参与神经元细胞的凋亡和存活反应，因此，PTS模型显示AP-1功能的两种可能性，凋亡和存活。本研究采用噪声诱导的暂时阈移（TTS）（已知不包括细胞凋亡的变化）来阐明AP-1对毛细胞存活的贡献。豚鼠暴露于110 dB SPL的4kHz频带噪声1至5小时，并使用Western印迹分析和免疫细胞化学证实了c-Fos的表达。Westem杂交结果显示c-Fos在耳蜗耳蜗的Corti器和外侧壁（包括血管纹）有表达，而在耳蜗蜗轴（包括螺旋神经节细胞）无表达。免疫细胞化学染色显示c-Fos仅在噪声暴露后表达。c-Fos主要表达于耳蜗基底回和第二回的Hensen细胞和Deiter细胞。由于阈值偏移是暂时的，c-Fos的表达被认为有助于Corti器官的存活或保护功能。少

项目成果

Ogawa,K, Takei,S, Inoue,Y, Kanzak,J.: "Effect of PGEI on idiopathic sudden sensorineural hearing loss:a double-blind study."Otol Neurotol. 23. 665-668 (2002)

Okawa,K、Takei,S、Inoue,Y、Kanzak,J.：“PGEI 对特发性突发感音神经性听力损失的影响：双盲研究。”Otol Neurotol。

Ogita,K, Okuda,H, Kitano,M, Fujinami,Y, Ozaki,K, Yoneda,Y.: "Localization of activator protein-1 complex with DNA binding activity in mitochondria of murine brain after in vivo treatment with kainate"J Neurosci. 22. 2561-2570 (2002)

Ogita,K, Okuda,H, Kitano,M, Fujinami,Y, Ozaki,K, Yoneda,Y.：“红藻氨酸体内处理后，具有 DNA 结合活性的激活蛋白 1 复合物在小鼠大脑线粒体中的定位”J

Ogita K, Okuda H et al.: "Lu vivo neuroprotective role of NMDA receptors against kainate-induced excitotoxicity in murine hippocampal pyramidal neurons"J Neurochem. 85. 1336-1346 (2003)

Ogita K、Okuda H 等人：“NMDA 受体对小鼠海马锥体神经元中红藻氨酸诱导的兴奋性毒性的体内神经保护作用”J Neurochem。

Ogawa K, Takei S et al.: "Effect of PGE1 on idiopathic sudden sensorineural hearig loss : a double-blind study"Otol Neurotol. 23. 665-668 (2002)

Okawa K、Takei S 等人：“PGE1 对特发性突发感音神经性听力损失的影响：双盲研究”Otol Neurotol。

Kanzaki,S, Ogawa,K, Camper,SA, Raphael,Y: "Transgene expression neonatal mouse inner ear explants mediated by first and advanced generation adebovirus vectors"Hear Res. 169. 112-120 (2002)

Kanzaki，S，Okawa，K，Camper，SA，Raphael，Y：“第一代和先进的腺病毒载体介导的转基因表达新生小鼠内耳外植体”Hear Res。