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題名 轉錄因子STAT1在大鼠空間學習與記憶形成的角色探討
Role of STAT1 in spatial memory formation in rats
作者 謝定佑
Hsieh,Ding You
貢獻者 李小媛
謝定佑
Hsieh,Ding You
關鍵詞 轉錄因子
學習與記憶
海馬迴
水迷津試驗
西方墨點法
即時定量聚合酶連鎖反應
基因啟動子
STAT1
leaning and memory
hippocampus
water maze
western blotting
real time-PCR
GAS
日期 2009
上傳時間 3-Sep-2013 14:05:13 (UTC+8)
摘要 STAT1是一個轉錄因子，在細胞生理功能中是非常重要的訊息傳遞者，在免疫系統具有抗病毒的角色，但是目前為止對於STAT1在中樞神經系統所扮演的角色仍不清楚。爲證實STAT1的表現與空間記憶的形成有關聯，我們將大白鼠分成兩組，一組為有訓練的組別，另一組則為無訓練的組別分別進行水迷津試驗，試驗完畢後取出大鼠的海馬迴CA1區域組織進行即時定量聚合酶連鎖反應與西方墨點法分析。結果顯示，經過水迷津訓練的刺激下，STAT1 mRNA與蛋白質分別減少約34 %及40 %，而STAT2 mRNA及蛋白質的表現則不受空間學習的影響。爲了進ㄧ步探討STAT1在空間學習記憶過程中所扮演的角色，實驗利用STAT1 siRNA轉染至海馬迴CA1區域抑制STAT1的表現，發現降低STAT1表現會促進大白鼠在水迷津試驗的學習能力，實驗同時也轉染STAT2 siRNA至CA1區域，結果顯示STAT2不參與大白鼠空間記憶的形成。本實驗室先前發現降低laminin β1表現量會促進大白鼠的空間學習記憶 (unpublished observation, 附錄二)，此外laminin β1基因啟動子上具有STAT1結合序列：interferon-γ activated site (GAS)。因此，實驗利用PC12細胞進行laminin β1報導基因分析，結果顯示STAT1會促進 laminin β1啟動子的轉錄活性。而爲了進一步探討在STAT1影響空間學習與記憶歷程中與laminin β1的關聯性，實驗利用STAT1 siRNA抑制大白鼠海馬迴CA1區STAT1的表現並促進空間學習與記憶的同時，發現laminin β1 mRNA及蛋白質表現量都受到STAT siRNA的抑制，而轉染野生型STAT1-Flag質體則會增加laminin β1 mRNA及蛋白質的表現量，顯示STAT1正向調控laminin β1的表現。本篇論文提出海馬迴CA1區域的STAT1參與動物空間學習與記憶的形成，其中可能與STAT1正向調控laminin β1的表現有關。
STAT1 is a signal transducer and transcription factor in the cell. Several reports have indicated that STAT1 plays a critical role in immune response against virus infection in animals. However, the role of STAT1 in the central nervous system is still unclear. In the present study, we aimed to examine the role of STAT1 involved in spatial memory formation in rat and the possible downstream gene that STAT1 regulates. Rats were randomly divided into the trained group and the non-trained group. Animals were subjected to water maze learning according to the previous behavioral paradigm. Their hippocampus CA1 tissues were dissected out for STAT1 mRNA level and protein level determination. Results indicated that spatial training markedly decreased STAT1 mRNA level and protein level in the CA1 area, but this change was not found for STAT2 mRNA and protein expression. To further confirm the role of STAT1 involved in spatial learning and memory, animals were transfected with STAT1 siRNA in the CA1 area. Results showed that STAT1 siRNA transfection significantly facilitated water maze performance, whereas their water maze performance under STAT2 siRNA transfection was not altered. Previous studies from our laboratory have demonstrated that laminin β1 impairs spatial memory formation in rat (unpublished observation). In addition, promoter analysis indicates that the laminin β1 promoter region contains two GAS elements, which is the STAT1/STAT1 and STAT1/STAT3 binding site. Results from luciferase reporter assay revealed that transfection of STAT1 siRNA decreased laminin β1 promoter activity, whereas transfection of STAT1 wild-type plasmid increased laminin β1 promoter activity. To further study the relationship between STAT1 and laminin β1 in spatial memory formation, we used STAT1 siRNA to knockdown STAT1 expression and these animals were subjected to spatial training. We then determined their laminin β1 expression. Results showed that the laminin β1 mRNA level and protein level were both significantly decreased by STAT1 siRNA transfection. Besides, STAT1 wild-type plasmid transfection increased laminin β1 mRNA level and protein level in the CA1 area associated with spatial memory impairment. These results together suggest that STAT1 negatively regulates spatial memory formation. Further, STAT1 may impair spatial memory formation through increased laminin β1 expression.
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描述 碩士
國立政治大學
生命科學研究所
96754004
98
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0096754004
資料類型 thesis
dc.contributor.advisor 李小媛zh_TW
dc.contributor.author (Authors) 謝定佑zh_TW
dc.contributor.author (Authors) Hsieh,Ding Youen_US
dc.creator (作者) 謝定佑zh_TW
dc.creator (作者) Hsieh,Ding Youen_US
dc.date (日期) 2009en_US
dc.date.accessioned 3-Sep-2013 14:05:13 (UTC+8)-
dc.date.available 3-Sep-2013 14:05:13 (UTC+8)-
dc.date.issued (上傳時間) 3-Sep-2013 14:05:13 (UTC+8)-
dc.identifier (Other Identifiers) G0096754004en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/59759-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 生命科學研究所zh_TW
dc.description (描述) 96754004zh_TW
dc.description (描述) 98zh_TW
dc.description.abstract (摘要) STAT1是一個轉錄因子，在細胞生理功能中是非常重要的訊息傳遞者，在免疫系統具有抗病毒的角色，但是目前為止對於STAT1在中樞神經系統所扮演的角色仍不清楚。爲證實STAT1的表現與空間記憶的形成有關聯，我們將大白鼠分成兩組，一組為有訓練的組別，另一組則為無訓練的組別分別進行水迷津試驗，試驗完畢後取出大鼠的海馬迴CA1區域組織進行即時定量聚合酶連鎖反應與西方墨點法分析。結果顯示，經過水迷津訓練的刺激下，STAT1 mRNA與蛋白質分別減少約34 %及40 %，而STAT2 mRNA及蛋白質的表現則不受空間學習的影響。爲了進ㄧ步探討STAT1在空間學習記憶過程中所扮演的角色，實驗利用STAT1 siRNA轉染至海馬迴CA1區域抑制STAT1的表現，發現降低STAT1表現會促進大白鼠在水迷津試驗的學習能力，實驗同時也轉染STAT2 siRNA至CA1區域，結果顯示STAT2不參與大白鼠空間記憶的形成。本實驗室先前發現降低laminin β1表現量會促進大白鼠的空間學習記憶 (unpublished observation, 附錄二)，此外laminin β1基因啟動子上具有STAT1結合序列：interferon-γ activated site (GAS)。因此，實驗利用PC12細胞進行laminin β1報導基因分析，結果顯示STAT1會促進 laminin β1啟動子的轉錄活性。而爲了進一步探討在STAT1影響空間學習與記憶歷程中與laminin β1的關聯性，實驗利用STAT1 siRNA抑制大白鼠海馬迴CA1區STAT1的表現並促進空間學習與記憶的同時，發現laminin β1 mRNA及蛋白質表現量都受到STAT siRNA的抑制，而轉染野生型STAT1-Flag質體則會增加laminin β1 mRNA及蛋白質的表現量，顯示STAT1正向調控laminin β1的表現。本篇論文提出海馬迴CA1區域的STAT1參與動物空間學習與記憶的形成，其中可能與STAT1正向調控laminin β1的表現有關。zh_TW
dc.description.abstract (摘要) STAT1 is a signal transducer and transcription factor in the cell. Several reports have indicated that STAT1 plays a critical role in immune response against virus infection in animals. However, the role of STAT1 in the central nervous system is still unclear. In the present study, we aimed to examine the role of STAT1 involved in spatial memory formation in rat and the possible downstream gene that STAT1 regulates. Rats were randomly divided into the trained group and the non-trained group. Animals were subjected to water maze learning according to the previous behavioral paradigm. Their hippocampus CA1 tissues were dissected out for STAT1 mRNA level and protein level determination. Results indicated that spatial training markedly decreased STAT1 mRNA level and protein level in the CA1 area, but this change was not found for STAT2 mRNA and protein expression. To further confirm the role of STAT1 involved in spatial learning and memory, animals were transfected with STAT1 siRNA in the CA1 area. Results showed that STAT1 siRNA transfection significantly facilitated water maze performance, whereas their water maze performance under STAT2 siRNA transfection was not altered. Previous studies from our laboratory have demonstrated that laminin β1 impairs spatial memory formation in rat (unpublished observation). In addition, promoter analysis indicates that the laminin β1 promoter region contains two GAS elements, which is the STAT1/STAT1 and STAT1/STAT3 binding site. Results from luciferase reporter assay revealed that transfection of STAT1 siRNA decreased laminin β1 promoter activity, whereas transfection of STAT1 wild-type plasmid increased laminin β1 promoter activity. To further study the relationship between STAT1 and laminin β1 in spatial memory formation, we used STAT1 siRNA to knockdown STAT1 expression and these animals were subjected to spatial training. We then determined their laminin β1 expression. Results showed that the laminin β1 mRNA level and protein level were both significantly decreased by STAT1 siRNA transfection. Besides, STAT1 wild-type plasmid transfection increased laminin β1 mRNA level and protein level in the CA1 area associated with spatial memory impairment. These results together suggest that STAT1 negatively regulates spatial memory formation. Further, STAT1 may impair spatial memory formation through increased laminin β1 expression.en_US
dc.description.tableofcontents 誌謝 I
中文摘要 II
英文摘要 IV
目錄 VI
圖次 XI
縮寫全名對照表 XII
第一章、緒論 1
第一節、 學習與記憶 1
ㄧ、 學習與記憶的定義 1
二、 學習與記憶的種類 1
三、 記憶形成之歷程 2
四、 參與學習與記憶的腦區 3
第二節、 海馬迴組織與學習記憶 4
ㄧ、 海馬迴的構造 4
二、 海馬迴的投射路徑 5
三、 海馬迴與空間學習記憶的關係 6
四、 學習記憶相關的動物行為實驗 7
第三節、 突觸可塑性 (synaptic plasticity) 8
第四節、 訊息傳遞與轉錄活化因子 (signal transducer and activator of transcription, STAT) 11
第五節、 STATs蛋白在細胞生理功能上所扮演的角色 14
第六節、 STAT1與STAT2蛋白質的細胞生理功能 15
ㄧ、 STAT1 15
二、 STAT2 18
第七節、 層黏蛋白 (Laminin，LN) 家族 19
ㄧ、 層黏蛋白的簡介 19
二、 層黏蛋白在神經系統中的表現與功能 20
三、 層黏蛋白β1與記憶的關係 22
第八節、 本論文之研究目的與策略 23
第二章、實驗材料與研究方法 24
第一節 實驗動物 24
第二節 海馬迴內質體基因轉染 (transfection) 或藥物注射 24
ㄧ、 立體定位手術 (stereotaxic surgery) 與埋管 24
二、 質體基因與聚乙烯亞胺 (polyethylenimine, PEI) 混合物的製備 25
三、 STAT1 siRNA與STAT2 siRNA的配製 26
四、 海馬迴CA1區域注射 26
第三節 免疫組織化學染色 (immunohistochemistry) 27
ㄧ、 組織切片的製備 27
二、 免疫組織化學染色 28
第四節 動物行為實驗：莫氏水迷津實驗 (Morris water maze) 29
ㄧ、 水迷津實驗器材 29
二、 隱藏式平台 (hidden platform) 水迷津學習試驗 29
三、 探測試驗 (probe trial) 30
四、 可見式平台 (visible platform) 水迷津試驗 31
五、 有訓練 (trained) 和無訓練 (non-trained) 的水迷津試驗 31
第五節 即時定量聚合酶連鎖反應 (real-time polymerase chain reaction, real time-PCR) 31
ㄧ、分離海馬迴 (hippocampus)、紋狀體 (striatum) 及杏仁核 (amygdala) 組織 32
二、 腦組織RNA之萃取 32
三、 反轉錄酵素 (reverse transcriptase) 反應 33
四、 即時定量聚合酶連鎖反應 (real-time polymerase chain reaction, real time-PCR) 33
第六節 西方墨點法 (western blot) 34
一、 萃取腦組織蛋白質 34
二、 蛋白質濃度測定法 35
三、 免疫沉澱反應 (immunoprecipitation, IP) 35
四、 STAT1 DNA 結合試驗 (STAT1 DNA binding assay) 36
五、 西方墨點法 37
第七節 層黏蛋白β1報告基因表現量分析 (reporter gene analysis) 39
一、 細胞培養皿之塗抹 (coating plate) 39
二、 活化冷凍細胞 39
三、 細胞培養 40
四、 層黏蛋白β1報告基因表現量分析 41
五、 冷凍保存細胞 42
第八節 統計分析 42
第三章、結果 44
第一節 水迷津試驗降低海馬迴CA1區域STAT1 mRNA及蛋白質的表現 44
第二節 海馬迴CA1區域內STAT1表現量降低會促進大白鼠空間記憶的形成 49
第三節 大白鼠CA1區域STAT2的表現量減少並不影響大白鼠空間記憶的形成 53
第四節 STAT1會影響laminin β1的啟動子促進laminin β1的轉錄活性 56
第五節 海馬迴CA1區域轉染STAT1 siRNA會抑制laminin β1的表現 59
第六節 海馬迴轉染野生型STAT1會促進laminin β1的表現 62
第四章、討論 65
第五章、結論 77
參考資料 78
附錄 88
附錄一、大白鼠經水迷津試驗會減低海馬迴CA1區域的laminin β1蛋白質的表現 88
附錄二、抑制海馬迴CA1區域laminin β1表現會促進空間記憶的形成 89
附錄三、大白鼠經水迷津試驗會減低海馬迴CA1區域的STAT3蛋白質的表現 90
附錄四、STATs蛋白質家族與其細胞生理功能 91
附錄五、層黏蛋白結構圖 92
附錄六、pRC/CMV質體結構圖 93		zh_TW
dc.format.extent 3386710 bytes-
dc.format.mimetype application/pdf-
dc.language.iso en_US-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0096754004en_US
dc.subject (關鍵詞) 轉錄因子zh_TW
dc.subject (關鍵詞) 學習與記憶zh_TW
dc.subject (關鍵詞) 海馬迴zh_TW
dc.subject (關鍵詞) 水迷津試驗zh_TW
dc.subject (關鍵詞) 西方墨點法zh_TW
dc.subject (關鍵詞) 即時定量聚合酶連鎖反應zh_TW
dc.subject (關鍵詞) 基因啟動子zh_TW
dc.subject (關鍵詞) STAT1en_US
dc.subject (關鍵詞) leaning and memoryen_US
dc.subject (關鍵詞) hippocampusen_US
dc.subject (關鍵詞) water mazeen_US
dc.subject (關鍵詞) western blottingen_US
dc.subject (關鍵詞) real time-PCRen_US
dc.subject (關鍵詞) GASen_US
dc.title (題名) 轉錄因子STAT1在大鼠空間學習與記憶形成的角色探討zh_TW
dc.title (題名) Role of STAT1 in spatial memory formation in ratsen_US
dc.type (資料類型) thesisen
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