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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉宏輝(Horng-Huei Liou) | |
| dc.contributor.author | Zhe-Wen Cai | en |
| dc.contributor.author | 蔡哲文 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:11:04Z | - |
| dc.date.available | 2024-08-28 | |
| dc.date.copyright | 2019-08-28 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-08-07 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78669 | - |
| dc.description.abstract | Dravet症候群是一種頑固型的癲癇疾病，80％以上的病患都是由於SCN1A基因發生突變而致病的；SCN1A編碼電壓敏感型鈉離子通道Nav1.1的α次單元，Nav1.1因基因突變而喪失功能會導致抑制型的神經元減少GABA的釋出，使得興奮型的神經元過度興奮造成癲癇的症狀；除了明瞭GABA的釋出減少可能是致病的原因之外，目前對於Dravet症候群之發病機制的了解還很薄弱。在我們實驗室過去的研究當中發現Scn1a+/-小鼠海馬迴的神經新生會不正常增加，且Scn1a+/-神經幹細胞有偏向增生及分化的趨勢；不正常增加的神經新生被認為會改變腦部結構造成自發性的重覆癲癇，因此我們推測除了GABA的釋出減少之外，不正常增加的神經新生也是造成Dravet症候群的頑固型癲癇之原因。如果能找到一個分子標的能同時調控神經元的興奮性與神經新生，再以適合的藥物控制，可能就會對Dravet症候群的癲癇症狀有良好的控制效果。哺乳動物雷帕黴素標靶蛋白(mTOR)已經被証實與腦部結構改變及癲癇的形成相關，且其抑制劑能夠降低興奮型神經元釋出榖胺酸(glutamate)，因此在本篇研究中，我們希望藉由測試mTOR抑制劑everolimus能否改善Scn1a+/-小鼠的癲癇症狀以及能否改善Scn1a+/-神經幹細胞偏向增生及分化的特性來評估everolimus治療Dravet症候群的潛力。我們觀察到短期給予everolimus確實能改善Scn1a+/-小鼠在高溫下的癲癇易感性，且在細胞實驗中everolimus能有效抑制Scn1a+/-神經幹的增生及分化。為了進一步了解everolimus抑制神經幹細胞增生及分化的機制，我們測試everolimus能否降低神經幹細胞中與神經新生相關的基因之表現量，結果顯示Scn1a+/-神經幹細胞之中的mTOR, Hif-1α以及Vegf-a有不正常增加的趨勢，而everolimus則能轉扭這些不正常的增加。以上實驗結果顯示everolimus能改善Scn1a+/-小鼠的癲癇症狀也能改善Scn1a+/-神經幹細胞偏向增生及分化的特性，everolimus對於治療Dravet症候群的是有潛力的。 | zh_TW |
| dc.description.abstract | Dravet syndrome is an epilepsy disorder results from a heterozygous loss-of-function mutation in SCN1A which encodes the α subunit of the voltage-gated sodium channel Nav1.1. The dysfunction of Nav1.1 in GABAergic inhibitory neurons in Dravet syndrome decreases the release of GABA and then causes excitatory neurons hyperexcitability. However, the pathogenesis of Dravet syndrome is still unclear. In our previous studies, we demonstrated that the dysfunction of Nav1.1 in neural stem cells (NSCs) significantly enhances the cellular proliferation and neural lineage differentiation. Abnormal neurogenesis is proposed to contribute to epileptogenesis and cause spontaneous recurrent seizures. We, therefore, hypothesize that the intractable epilepsy in Dravet syndrome may be caused not only by a decreased GABA-mediated inhibition but also by enhanced abnormal neurogenesis. To ameliorate seizures in Dravet syndrome, it is necessary to find a target which is involved in regulating neuron excitability and neurogenesis. The mammalian target of rapamycin (mTOR)-mediated pathway has recently emerged as a critical regulator in epileptogenesis. Moreover, the mTOR inhibitor has been shown to decrease synaptic transmission in glutamatergic neurons. In this study, to evaluate the potential effect of mTOR inhibitor, everolimus, in ameliorating intractable epilepsy in Dravet syndrome. We first examined the anticonvulsant ability of everolimus in Scn1a+/- mice. In addition, we also investigated the effect of everolimus in NSCs obtained from Scn1a+/- mouse brain. Furthermore, we attempte to uncover the mechanism of mTOR signaling in neurogenesis in Dravet syndrome. Our results indicate that the everolimus remarkably attenuates seizure susceptibility in Scn1a+/- mice. Moreover, everolimus inhibits proliferation and differentiation in Scn1a+/- NSCs. We also obtained the abnormal increasing expression level of mTOR, Hif-1α and Vegf-a which related to epileptogenesis in Scn1a+/- NSCs, and these abnormal increasing levels were reversed by everolimus. These results suggest that the everolimus as a potential candidate treatment drugs for therapy Dravet syndrome. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:11:04Z (GMT). No. of bitstreams: 1 ntu-108-R06443020-1.pdf: 5181644 bytes, checksum: c245b50e941507168563d0860122d4df (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 摘要 III
Abstract IV 圖目錄 VI 縮寫表 VIII 第一章 緒論(Introduction) 1 第一節 Dravet症候群與其成因 1 第二節 Dravet症候群的小鼠模型 2 第三節 神經新生與epilpeptogenesis的關聯 3 第四節 mTOR pathway在癲癇中扮演的角色 5 第五節 可能對癲癇有影響的mTOR pathway下游訊息傳遞路徑 7 第六節 研究動機與目的 9 第二章 實驗材料與方法(Materials and methods) 11 第一節 實驗動物 11 第二節 高溫誘導癲癇行為實驗 11 第三節 冷凍切片與組織染色 12 第四節 神經幹細胞增生培養 12 第五節 神經幹細胞分化培養與細胞染色 14 第六節 即時聚合酶鏈鎖反應(Quantitative real time polymerase chain reaction;qPCR) 15 第七節 統計分析 15 第三章 結果(Result) 16 第一節 Everolimus改善Scn1a+/-小鼠的癲癇易感性 16 第二節 Everolimus抑制Scn1a+/-神經幹細胞增生 19 第三節 Everolimus抑制Scn1a+/-神經幹細胞分化為神經元 21 第四節 Everolimus抑制mTOR pathway下游與神經新生相關的基因表現 23 第四章 討論(Discussion) 28 第一節 總述 28 第二節 Everolimus抑制神經元興奮性並改善Scn1a+/-小鼠的癲癇易感性 29 第三節 mTOR pathway與GABA在神經新生的角色 31 第四節 mTOR pathway藉由多種路徑調控神經新生 33 第五節 未來展望 36 第五章 圖表(Figure and table) 38 參考文獻(Reference) 64 表一 免疫組織與細胞染色使用之抗體 71 表二 即時聚合酶鏈鎖反應(qPCR)使用之primer 71 | |
| dc.language.iso | zh-TW | |
| dc.subject | mTOR | zh_TW |
| dc.subject | Dravet症候群 | zh_TW |
| dc.subject | 癲癇 | zh_TW |
| dc.subject | SCN1A | zh_TW |
| dc.subject | 神經幹細胞 | zh_TW |
| dc.subject | 神經新生 | zh_TW |
| dc.subject | mTOR | en |
| dc.subject | SCN1A | en |
| dc.subject | Dravet syndrome | en |
| dc.subject | epilepsy | en |
| dc.subject | neurogenesis | en |
| dc.subject | neural stem cell | en |
| dc.title | Dravet症侯群小鼠之癲癇易感性及癲癇形成之研究 | zh_TW |
| dc.title | Study of the mechanism in seizure susceptibility and epileptogenesis in Dravet syndrome mice | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 符文美(Wen-Mei Fu),林琬琬(Wan-Wan Lin) | |
| dc.subject.keyword | Dravet症候群,癲癇,SCN1A,神經幹細胞,神經新生,mTOR, | zh_TW |
| dc.subject.keyword | Dravet syndrome,epilepsy,SCN1A,neural stem cell,neurogenesis,mTOR, | en |
| dc.relation.page | 71 | |
| dc.identifier.doi | 10.6342/NTU201902753 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-08-07 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| dc.date.embargo-lift | 2024-08-28 | - |
| 顯示於系所單位： | 藥理學科所 | |
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