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研究生:施漢鵬
研究生(外文):Han-Peng Shih
論文名稱:SPAK在中樞神經系統的功能角色之開發: 行為分析、多巴胺回收和發炎反應
論文名稱(外文):Exploring The Functional Role of SPAK in Central Nervous System:Behavioral Analysis,Dopamine Uptake and Inflammatory Responses.
指導教授:黃春霖黃春霖引用關係劉亞平劉亞平引用關係
指導教授(外文):Chuen-Lin HuangYia-Ping Liu
口試委員:黃春霖劉亞平楊瀅臻黃乃瑰陳思甫
口試委員(外文):Chuen-Lin HuangYia-Ping LiuYing-Chen YangNai-Kuei HuangSzu-Fu Chen
口試日期:2014-05-12
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:87
中文關鍵詞:SPAK
外文關鍵詞:SPAK
相關次數:
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SPAK (Ste20-related Proline Alanine rich Kinase)是廣泛存在於哺乳動物的蛋白激酶,隸屬MAPK(mitogen-activated protein kinase)的Ste20超級家族成員,先前的研究已知它們會藉由調控細胞膜上的鈉/鉀/氯離子的共同轉運子(例如: NKCC1、KCC2、NCC及KCC2)的活性以調節在中樞和周邊神經系統的GABA神經活性。SPAK除了表現在腎臟和心臟等器官外,在中樞大腦中亦有大量的表現。近年的研究指出過度表現SPAK會有促進結腸發炎的現象,反之,剔除SPAK在小腸中則具有抗發炎的作用。然而SPAK在大腦中的真正功能為何確仍然未知。本研究利用SPAK 基因剔除(SPAK(-/-))小鼠模式進行動物行為試驗、並針對大腦紋狀體多巴胺轉運子(Dopamine transporter; DAT)的活性與生化分析以及誘發大腦發炎等三個方向作為探討SPAK在中樞神經系統上可能的角色之研究議題。

首先,在動物行為的實驗結果顯示SPAK (-/-)小鼠在獨木橋的行為測試上表現較野生型小鼠差,在水迷津試驗上表現出較差的學習記憶能力,而在強迫游泳的分析上表現出較長的不動時間。由上述結果指出SPAK(-/-)小鼠在平衡與運動協調以及空間記憶的能力上都呈現有明顯的缺損情形。此外,SPAK(-/-)小鼠也表現出具有憂鬱的傾向。然而SPAK(-/-)小鼠在加速行滾輪試驗、基礎動向試驗、吊尾試驗與懸吊試驗等項目的分析與野生型小鼠相比較則無明顯差異。其次,在多巴胺轉運子活性與生化分析上發現SPAK(-/-)母鼠的細胞膜上DAT的活性與其蛋白表現量均呈現顯著較低的現象,而公鼠則無明顯差異。最後,利用腹腔注射內毒素(Lipopolysaccharide; LPS)與除草劑百草枯(Paraquat; PQ)促使大腦發炎的研究上,透過免疫螢光組織切片染色結果顯示SPAK主要是表現在Microglia和Neuron上,而少部分則有表現在Astrocyte上。有趣的是 SPAK (-/-)小鼠在PQ及(LPS+PQ)的處理下,在黑質體區的多巴胺神經細胞存活數目皆多於野生型。野生型小鼠在(LPS+PQ)處理下發現促發炎的轉錄蛋白分子NF-B (p65)進入Microglia細胞核的數量有明顯增加的現象。令人注意的是在(LPS+PQ)處理組發現,SPAK(-/-)小鼠的大腦皮質與紋狀體區其NF-B (p65)進入Microglia細胞核的數量相較於野生型小鼠而言卻有顯著減少的趨勢,然而在NF-B (p65)進入Neuron細胞核的數量並無顯著差異。

綜合本研究結果指出SPAK在中樞大腦中具有調節運動平衡、空間記憶學習能力與抗憂鬱的功能。而在SPAK(-/-)母鼠上發現有較低的DAT活性意味著雌激素可能透過SPAK而影響多巴胺的神經傳遞。此外,野生型小鼠處理(LPS+PQ)會誘發NF-B (p65)進入Microglia細胞核的現象,卻在SPAK剔除小鼠上有顯著減少。此實驗結果指出在大腦中若是抑制或降低SPAK的表現很可能會具有抗發炎的作用。

SPAK (Ste20-related Proline Alanine rich Kinase) is widely present in mammalian protein kinase, belongs the MAPK Ste-20 superfamily members. Previous studies have known that SPAK can modulate the activity of Na+/ K+/ Cl- co-transporters, which locate on plasma membrane, to regulate the GABAergic activity. Except SPAK is riched in heart and kidney, it has been reported that expressed in brain. Recent studies have demonstrated that overexpression of SPAK exacerbates experimental colitis while knockout of SPAK attenuates intestinal inflammation in mice. However, the real function of SPAK in the brain is still unknown. To investigate the possible role of SPAK in the brain in this study, we design three directions, respectively, animal behavioral tests, the striatal dopamine transporter (DAT) activity and biochemical analysis as well as brain inflammation by using SPAK knockout (SPAK (-/-)) mice to access these questions.
First, results in animal behavior, SPAK (-/-) mice displayed poor performance in the beam walk test and showed poor learning and memory in the Morris water maze test than wild type. In the forced swimming test, SPAK (-/-) mice appeared more immobile time than wild type. However, there is no difference in accelerating rotarod-, locomotion-, tail suspension- and wire hang- test compare with wild type. Secondly, we found that female SPAK (-/-) mice appear lower DAT activity compared with wild type but no difference in male SPAK (-/-) mice. Using biochemical analysis showed the lower amount of DAT in synaptosomal membrane in female SPAK (-/-) mice. SPAK is mainly expressed in the cytosol of microglia and neuron and fewer signals of SPAK also appeared in astrocyte by immunofluorescence staining of brain sections. Finally, we use intraperitoneal injection of lipopolysaccharide (LPS) and paraquat (PQ) to induce brain inflammation. Under PQ and (LPS+PQ) treatment, the survival number of dopamine neurons in the substantia nigra in SPAK (-/-) mice were more than wild type. (LPS+PQ) treatment significantly increased the cell number which NF-B (p65) translocated into the microglia nucleus in wild type mice. Interestingly, under (LPS+PQ) treatment, reduction of the number of NF-B (p65) into the microglia nucleus in the cerebral cortex and striatum of SPAK (-/-) mice were appeared, however, no significant difference occurred in neuron.
These results indicate SPAK (-/-) mice present significant defects in balance and motor coordination, impairment of learning ability and spatial memory. SPAK (-/-) mice also showed a tendency of depression. Lower DAT activity was found in female SPAK (-/-) mice suggested that estrogen might be involved in SPAK-regulated dopamine neurotransmission. In addition, (LPS+PQ)-induced NF-B (p65) into the microglia nucleus was markedly attenuated in SPAK (-/-) mice implied that inhibition or reduction of SPAK might play an anti-inflammatory effect in the brain.

目錄.............................1
圖目錄............................3
中英文縮寫對照表....................6
中文摘要...........................7
英文摘要...........................8
第一章 緒論.........................9
第一節 SPAK (STE20/SPS1-related proline/alanine-rich kinase)的發現……………9
第二節 SPAK分佈位置與NKCCs/NCCs/KCCs調控功能……………………………10
第三節 SPAK基因剔除小鼠.................................................................................12
第四節 Mitogen-activated protein kinase (MAPK)與多巴胺轉運.....................…13
第五節 百草枯paraquat (PQ)與帕金森氏症Parkinson's disease (PD)………….....14
第六節 SPAK與發炎.....................................14
第七節 實驗目的…………………………………………………………….………………………………………………….......................................15
第二章 實驗材料與方法...........................................................................................16
第一節 實驗材料.....................................................................................................16
壹、實驗動物………………………………………………………………………………………..…………….16
貳、實驗儀器設備……………………………………………………………………………….…………….16
參、實驗抗體…………………………………………………………………………………….……………….17
肆、實驗試劑………………………………………………………………………………………………….….18
第二節、實驗方法與設計.......................................................................................18
壹、動物行為實驗.................................................................................................18
一、.加速型滾輪測試 (Accelerating rotarod test) ............................................18
二、獨木橋試驗(Beam walk test) .....................................................................19
三、曠野試驗(Open field locomotion test)........................................................19
四、強迫游泳試驗(Forced swim test ) ..............................................................19
五、懸尾試驗(Tail-suspension test ) ..................................................................20
六、吊線試驗(Wire hang test) ............................................................................20
七、莫式水迷津(Morris Water Maze test ).........................................................20
貳、動物組織抽取Genomic DNA...........................................................................21
參、聚合連鎖反應(Polymerase chain reaction, PCR ) .............................................21
肆、DNA電泳分析...................................................................................................22
伍、小鼠福馬林灌流.................................................................................................22
陸、免疫組織切片與染色.........................................................................................23
捌、西方墨點法(Western blot) .................................................................................24
玖、誘導大腦發炎小鼠模式.....................................................................................25
拾、多巴胺活性測試...........................................................................................26
拾壹、統計分析……………………………………………………………………………………………...……26
第三章 實驗結果.................................................................................................27
第一節 鑑定野生型、SPAK (+/-) 和SPAK (-/-)小鼠之基因型.........................27
第二節 測試SPAK (-/-)小鼠的運動協調能力。.................................................27
第三節 測試SPAK (-/-)小鼠憂鬱傾向........................................................28
第四節試SPAK (-/-)小鼠對於空間記憶與學習的影響。...................................29
第六節 檢測SPAK (-/-)小鼠的多巴胺轉運子活性。.........................................29
第七節 野生型與SPAK(-/-)小鼠大腦內Microglia、Astrocyte、Neuron和多巴胺神經元(Dopaminergic neuron)細胞數目的基本鑑定。................................................................................30
第八節 野生別投予Saline、LPS、PQ和(LPS+PQ)後,獨木橋試驗及Dopaminergic neuron免疫組織螢光染色的分析結果。........................31
第九節 野生型和SPAK (-/-)小鼠在投予saline後,在大腦皮質區和紋狀體區的
microglia、astrocyte與neuron其NF-B入核現象之免疫組織螢光染色分析結果。................................................................................................31
第十節 野生型和SPAK (-/-)小鼠在投予LPS後,在大腦皮質區和紋狀體區的
microglia、astrocyte與neuron其NF-B入核現象之免疫組織螢光染色的分析
結果。.............................................................................................32
第十一節 野生型和SPAK (-/-)小鼠在投予PQ後,在大腦皮質區和紋狀體區的
microglia、astrocyte與neuron其NF-B入核現象之免疫組織螢光染色的分析
結果。.............................................................................................32
第十二節 野生型和SPAK (-/-)小鼠在投予LPS+PQ後,在大腦皮質區和紋狀
體區的microglia、astrocyte與neuron其NF-B入核現象之免疫組織螢光染色
的分析結果。.........................................................................................................35
第四章 討論...............................................................................................................36
第五章 結論...............................................................................................................39
第六章 參考文獻.......................................................................................................40

圖目錄
圖一、不同基因型小鼠其Genomic DNA 做PCR反應的電泳分析結果。………45
圖二、三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)在加速型滾輪測試(Rotarod Test)的分析結果。…………………………..….…………………….46
圖三、三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)在獨木橋試驗(Beam Walk Test)的分析結果。…………..............................................47
圖四、三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)在曠野試驗( Open Field Locomotion Test)的分析結果。………...……………………………48
圖五、三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)在懸尾試驗(Tail Suspension Test)的分析結果。……...……………………………………………49
圖六、三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)在強迫游泳試驗(Force Swimming Test)的分析結果。………………………………....………50
圖七、三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)在莫式水迷津試驗( Morris Water Maze)的分析結果。.……………………..…………………51
圖八、三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)在莫式水迷津試驗中小鼠游泳的軌跡圖。.…………….........……………………………………52
圖九、三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)在吊線試驗(Wire Hang)的分析結果。.………………………..............................……………53
圖十、三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)在鼠腦紋狀體多巴胺轉運子活性的分析結果。….....................……………………........54
圖十一、運用西方墨點法檢測三種不同基因型的小鼠,包括野生型(Wild Type)、SPAK(+/-)與SPAK(-/-)其小鼠大腦紋狀體製備的synaptosomes膜上的DAT、NKCC1和KCC2之蛋白質表現量。……………………………………………………………….…..55
圖十二、運用免疫組織螢光染色分析野生型與SPAK(-/-)小鼠大腦內Microglia、Astrocyte、Neuron和Dopaminergic neuron細胞數量上的差異。.........................56
圖十三、運用免疫組織螢光染色分析野生型小鼠大腦皮質區,SPAK在Microglia表現情形。…………………………………………………………………………………………………….………..57
圖十四、運用免疫組織螢光染色分析野生型小鼠大腦皮質區,SPAK在Neuron表現情形。……………………………………………………………………………………………………………..58
圖十五、運用免疫組織螢光染色分析野生型小鼠大腦皮質區,SPAK在Astrocyte表現情形。……………………………………………………………………………………………………………..59
圖十六、運用免疫組織螢光染色分析野生型小鼠大腦皮質區,SPAK表現在Microglia、 Neuron和Astrocyte的情形。…………………………………………………………..60
圖十七、野生型和SPAK (-/-)小鼠,分別投予Saline、LPS、PQ和(LPS+PQ)後,在獨木橋試驗的分析結果。……………………………………………………………………………………61
圖十八、野生型和SPAK (-/-)小鼠分別投予Saline、LPS、PQ和(LPS+PQ)後,在黑質體區多巴胺神經元之免疫組織螢光染色的分析與計數量化之結果。………….62
圖十九、野生型和SPAK (-/-)小鼠分別投予Saline後,位於鼠腦皮質區的Microglia與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。……………………………………………………………………………………………………...........………..64
圖二十、野生型和SPAK (-/-)小鼠分別投予LPS後,位於鼠腦皮質區的Microglia與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。……………………………………….……………………………………………………………...........………..65
圖二十一、野生型和SPAK (-/-)小鼠分別投予PQ後,位於鼠腦皮質區的Microglia與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。…………………………………………………………………………………………………………...........…..66
圖二十二、野生型和SPAK (-/-)小鼠分別投予(LPS+PQ)後,位於鼠腦皮質區的Microglia與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。…………………………………………………………………………………………………….....………..67
圖二十三、野生型和SPAK (-/-)小鼠分別投予Saline後,位於鼠腦皮質區的Astrocyte與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。………………………………………………………………………………………………………....……..68
圖二十四、野生型和SPAK (-/-)小鼠分別投予LPS後,位於鼠腦皮質區的Astrocyte與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。…………………………………………………………………………………………………………............…..69
圖二十五、野生型和SPAK (-/-)小鼠分別投予PQ後,位於鼠腦皮質區的Astrocyte與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。……………………………………………………………………………………………………………….......…..70
圖二十六、野生型和SPAK (-/-)小鼠分別投予 (LPS+PQ)後,位於鼠腦皮質區的Astrocyte與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。………………………………………………………………………………………………………….......…71
圖二十七、野生型和SPAK (-/-)小鼠分別投予Saline後,位於鼠腦皮質區的Neuron與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。……………………………………………………………………………………………………….....…………….72
圖二十八、野生型和SPAK (-/-)小鼠分別投予LPS後,位於鼠腦皮質區的Neuron與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。……………………………………………………………………………………………….......………………….73
圖二十九、野生型和SPAK (-/-)小鼠分別投予PQ後,位於鼠腦皮質區的Neuron與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。………………………………………………………………………………………………………......…………..74
圖三十、野生型和SPAK (-/-)小鼠分別投予LPS+PQ後,位於鼠腦皮質區的Neuron與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。…………………………………………………………………………………………………………....………….75
圖三十一、野生型和SPAK (-/-)小鼠分別投予Saline後,位於鼠腦紋狀體區的Microglia與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。………………………………………………………………………………………………....……………..76
圖三十二、野生型和SPAK (-/-)小鼠分別投予LPS後,位於鼠腦紋狀體區的Microglia與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。…………………………………………………………………………………………………....…………..77
圖三十三、野生型和SPAK (-/-)小鼠分別投予PQ後,位於鼠腦紋狀體區的Microglia與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。………………………………………………………………………………………………………...………78
圖三十四、野生型和SPAK (-/-)小鼠分別投予LPS+PQ後,位於鼠腦紋狀體區的Microglia與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。……………………………………………………………………………………………………..………….79
圖三十五、野生型和SPAK (-/-)小鼠分別投予Saline後,位於鼠腦皮質區的Astrocyte與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。……………………………………………………………………………………………………..………….80
圖三十六、野生型和SPAK (-/-)小鼠分別投予LPS後,位於鼠腦紋狀體區的Astrocyte與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。…………………………………………………………………………………………………...…………….81
圖三十七、野生型和SPAK (-/-)小鼠分別投予PQ後,位於鼠腦紋狀體區的Astrocyte與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。……………………………………………………………………………………………………….………..82
圖三十八、野生型和SPAK (-/-)小鼠分別投予LPS+PQ後,位於鼠腦紋狀體區的Astrocyte與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。………………………………………………………………………………………………..………………..83
圖三十九、野生型和SPAK (-/-)小鼠分別投予Saline後,位於鼠腦紋狀體區的Neuron與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。………………………………………………………………………………………………………..……………84
圖四十、野生型和SPAK (-/-)小鼠分別投予LPS後,位於鼠腦紋狀體區的Neuron與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。…………………………………………………………………………………………………………………………85
圖四十一、野生型和SPAK (-/-)小鼠分別投予PQ後,位於鼠腦紋狀體區的Neuron與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。…………………………………………………………………………………………………………………………86
圖四十二、野生型和SPAK (-/-)小鼠分別投予LPS+PQ後,位於鼠腦紋狀體區的Neuron與促發炎轉錄因子NFB (p65)在免疫組織螢光染色的分析與計數量化之結果。……………………………………………………………………………………………………………………..87




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