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Identification and analysis of genes induced in peripheral nerve after axotomy using cDNA microarrays

使用cDNA微阵列鉴定和分析轴突切除术后周围神经诱导的基因

基本信息

批准号：
16591793
负责人：
HOSOKAWA Ko
金额：
$ 2.3万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591793/
关键词：
peripheral nerve regeneration sciatic nerve cyclin-dependent kinase inhibitor p21 Rho kinase inhibitor fasudil Slit-Robo facial nerve slit growth cone 反発因子 in situ hybridization radial growth neurofilament

项目摘要

It is generally known that injured peripheral axons regenerate successfully as oppose to central axons. However, complete functional recovery is rarely achieved. To solve this problem, we identified 500 genes induced in peripheral nerve after axotomy using cDNA microarrays in a previous study. The purpose of this project was to analyze the precise function of these genes. The main findings were as follows. 1. Sciatic nerve injury models were created on the p21 knock out mice and it was found that p21, which is a potent Rho kinase inhibitor, regulates radial growth of regenerating axons, thereby promoting functional recovery. Hyperphosphorylation of the neurofilament heavy chain subunits was considered to be the main reason for the impaired radial growth in the p21 knock out mice. 2. The clinically tested Rho-associated kinase inhibitor fasudil hydrochloride was applied to rat peroneal nerve injury models. After injury, significantly accelerated functional recovery was achieved in the fasudil treated animals as compared with control animals. 3. The mRNA expression changes of Slit-Robo signal molecules, known as axonal guidance cues, were examined using in situ hybridization. After transection of a rat facial nerve, up-regulation of slitl expression and down-regulation of slit2 expression were found in the facial nucleus. In contrast, both expressions were up-regulated in the distal Schwann cells.

众所周知，与中央轴突相反，受损的外周轴突成功再生。然而，很少能实现完全的功能恢复。为了解决这个问题，我们在以前的研究中使用cDNA微阵列鉴定了500个轴突切断后在周围神经中诱导的基因。该项目的目的是分析这些基因的精确功能。主要调查结果如下。1.在p21敲除小鼠上建立坐骨神经损伤模型，并且发现作为有效Rho激酶抑制剂的p21调节再生轴突的放射状生长，从而促进功能恢复。神经丝重链亚基的过度磷酸化被认为是p21基因敲除小鼠放射状生长受损的主要原因。2.将临床试验的Rho相关激酶抑制剂盐酸法舒地尔应用于大鼠腓总神经损伤模型。损伤后，与对照动物相比，法舒地尔治疗动物的功能恢复显著加速。3.使用原位杂交检测了Slit-Robo信号分子（称为轴突引导线索）的mRNA表达变化。面神经切断后，面神经核中slit 1表达上调，slit 2表达下调。相反，这两种表达在远端雪旺细胞中上调。