中国科学院上海生命科学研究院神经科学研究所机构知识库
Advanced  
SIBS OpenIR  > 神经所(总)  > 学位论文
Title: 转录抑制因子REST/NRSF在颞叶癫痫发生过程中的作用研究
Author: 胡晓玲
Degree Level: 博士
Issued Date: 2009-12-03
Degree Grantor: 中国科学院上海生命科学研究院
Place of Degree Grantor: 上海生命科学研究院
Supervisor: 熊志奇
Keyword: 颞叶癫痫 ; REST/NRSF ; 生酮饮食 ; 2DG ; 丙酮 ; BDNF ; trkB
Alternative Title: The role of transcriptional repressor REST/NRSF in temporal lobe epilepsy (TLE)
Major: 神经生物学
Abstract: 癫痫是一种以反复发作的抽搐为主要临床特征,同时伴随大脑神经元广泛同步放电的慢性神经系统异常。颞叶癫痫是临床上最常见的难治性癫痫,因其癫痫灶位于大脑的颞叶结构如海马,杏仁核等而得名。尽管有各种抗癫痫药物应用于 临床,仍有30%的病人其癫痫发作无法控制。癫痫治疗上的困难主要源于癫痫的产生机制不清。本实验主要从以下两个方面探讨了颞叶癫痫发生的相关因素:(1)、转录抑制因子REST/NRSF在颞叶癫痫发生过程中所起的作用。虽然REST/NRSF的mRNA在成年小鼠的大脑中基础表达水平很低,但是在癫痫发作过程中其表达却明显增高。在成年小鼠中,选择性地敲除前脑兴奋性神经元REST/NRSF基因后,癫痫发生过程明显增快,同时伴有海马齿状回苔藓纤维出芽的增多。但无论是在较少细胞死亡的电刺激点燃模型还是有较多细胞死亡的KA诱导的强直癫痫模型中,敲除小鼠和对照小鼠的细胞死亡并无显著差异。进一步研究发现,NRSF所调控的靶基因L1cam、FGF14、BDNF 和TrkB的mRNA表达在敲除小鼠中有明显增高。这些结果提示REST/NRSF的存在对于抑制癫痫的发展和恶化有重要作用。(2)、应用NRSF敲除小鼠研究生酮饮食及与其代谢相关的两种药物糖代谢抑制剂2脱氧葡萄糖(2DG)和脂肪代谢的终产物丙酮在癫痫发生过程中的作用。结果显示2DG的抗癫痫作用在NRSF敲除后消失,而丙酮和生酮饮食的抗癫痫作用机制却并不一致。以上结果使我们在分子和细胞水平上对颞叶癫痫的发生机制有了更进一步的认识,这些工作无论是在认识大脑功能方面还是在疾病治疗方面都具有积极意义。
English Abstract: Epilepsy is a chronic neurological disease characterized by the recurrent of spontaneous seizures in behavior. Temporal lobe epilepsy (TLE) is most common and drug-resistant type of adult focal epilepsy. To understand the mechanism underlying epileptogenesis, we explored the role of transcription repressor neuron restrictive silence factor (NRSF) also named REST in epileptogenesis. (1), The expression of REST/NRSF is decreased after differentiation of neuron. However, it has been upregulated during seizures activity. The limbic epileptogenesis has been greatly accelerated when we conditionally knockout (cKO) REST/NRSF in excitatory neuron of forebrain in adult mice. This phenomenon accompanied with increased mossy fiber sprouting in cKO mice. Interesting, we did not find any significant difference of cell death between cKO and control mice in kindling and KA model. Subsequently, we found mRNA expression of four NRSF regulated target genes L1cam, FGF14, BDNF, TrkB significantly upregulated in cKO mice. (2), Recently, a literature report that glycolytic inhibitor 2-deoxy-D-glucose impaired epileptogenesis by recruiting CtBP dependent REST/NRSF suppressing complex to remodel chromatin structure. By conditional deletion of REST/NRSF, we found REST/NRSF mediated transcriptional repression is required for antiepileptic effect of 2DG, but not acetone and ketogenic diet. Taken together, these results indicated that REST/NRSF serves as an intrinsic suppressor in epileptogenesis and is required for antiepileptic effect of 2DG but not acetone and ketogenic diet.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2397
Appears in Collections:神经所(总)_学位论文

Files in This Item:
File Name/ File Size Content Type Version Access License
10001_200418010015026胡晓玲_paper.pdf(1834KB)----暂不开放 联系获取全文

Recommended Citation:
转录抑制因子REST/NRSF在颞叶癫痫发生过程中的作用研究.胡晓玲[d].中国科学院上海生命科学研究院,2009.20-25
Service
Recommend this item
Sava as my favorate item
Show this item's statistics
Export Endnote File
Google Scholar
Similar articles in Google Scholar
[胡晓玲]'s Articles
CSDL cross search
Similar articles in CSDL Cross Search
[胡晓玲]‘s Articles
Related Copyright Policies
Null
Social Bookmarking
Add to CiteULike Add to Connotea Add to Del.icio.us Add to Digg Add to Reddit
所有评论 (0)
暂无评论
 
评注功能仅针对注册用户开放,请您登录
您对该条目有什么异议,请填写以下表单,管理员会尽快联系您。
内 容:
Email:  *
单位:
验证码:   刷新
您在IR的使用过程中有什么好的想法或者建议可以反馈给我们。
标 题:
 *
内 容:
Email:  *
验证码:   刷新

Items in IR are protected by copyright, with all rights reserved, unless otherwise indicated.

 

 

Valid XHTML 1.0!