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研究生:王靖雯
研究生(外文):Ching-WenWang
論文名稱:丙戊酸抑制LPS活化微膠細胞的P2X4受體與腫瘤壞死因子基因表現之研究
論文名稱(外文):Downregulation of purinergic P2X4 receptor and TNF-α in LPS-activated microglia by valproic acid
指導教授:曾淑芬曾淑芬引用關係
指導教授(外文):Shun-Fen Tzeng
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生命科學系碩博士班
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:68
中文關鍵詞:微膠細胞脂多醣丙戊酸P2X4受體
外文關鍵詞:microgliaLPSvalproic acidP2X4R
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微膠細胞為中樞神經系統中相當於免疫系統的巨噬細胞,微膠細胞的功能對於受損後中樞神經系統組織碎片的清除與重建而言是非常重要的。丙戊酸可做為histone deacetylase的抑制劑,在臨床上被用來做為一種抗痙孿與穩定情緒的藥物以治療癲癇與躁鬱症,亦被指出對於神經系統損傷後所造成的神經病理性疼痛有治療的效果。近幾年來研究指出,活化的微膠細胞P2X4受體(P2X4R)參與神經病理性疼痛的發展與維持。實驗室先前研究發現,丙戊酸能抑制脊髓損傷造成的微膠細胞P2X4R大量表現。基於此,本篇的研究目的主要是想透過in vitro的方式,利用活化微膠細胞以模擬發炎的情況下,探討丙戊酸是否調控微膠細胞P2X4R的表現並找出可能參與的訊息傳遞途徑。在Iba-1染色實驗觀察到,丙戊酸處理之下並不影響以LPS活化微膠細胞的細胞型態。根據microarray的結果發現,以細菌內毒素脂多醣(LPS)刺激的微膠細胞,其P2X4R的表現量為其他P2X受體之冠,丙戊酸會抑制由LPS活化微膠細胞的P2X4R mRNA表現量。microarray的結果亦發現,微膠細胞以LPS處理之下,調控前發炎因子的表現,其中腫瘤壞死因子(TNF-α)的表現則被丙戊酸所抑制。文獻指出,以丙戊酸處理未受刺激的微膠細胞藉由p38 MAPK的活化而導致細胞凋亡。因此,接著探討丙戊酸抑制活化的微膠細胞P2X4R與TNF-α mRNA表現量是否透過p38 MAPK的調控。結果指出,丙戊酸處理之下會增加p38 MAPK蛋白質磷酸化的表現量。前處理p38 MAPK的抑制劑SB2035802,可回升由丙戊酸所抑制的P2X4R與TNF-α mRNA表現量。綜合以上結果指出,丙戊酸藉由p38 MAPK的活化造成P2X4R與TNF-α mRNA表現量下降。
Microglia, the resident macrophages in the central nervous system (CNS), play the important role in neuropathogenesis and tissue debris removal after CNS injury. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is clinically prescribed as anti-seizure drugs to epilepsy, bipolar disorders and in other neurological condition such as neuropathic pain. Recently, a great deal of attention has been focused on the relation between neuropathic pain and microglia activated through purinergic P2X4 receptors. P2X4R action is involved in microglia activation and microglia-associated induction of neuropathic pain. Accordingly, we attempted to examine whether VPA affect P2X4R expression in activated microglia. Immunostaining indicated that VPA treatment had no effect the on cell morphology in endotoxin lipopolysaccharide(LPS)-activated microglia. Through gene expression microarray, we found that among P2 purinergic receptors a P2X isotype, P2X4R, is exclusively expressed in microglia activated by LPS. We found that LPS-induced increase in P2X4R mRNA expression was blocked by exposure to VPA. The results from the comparative gene microarray analysis also showed that a set of proinflammatory mediators, such as tumor necrosis factor alpha (TNF-α) increased in microglia by LPS stimulation was reduced by treatment with VPA. We also found that exposure to VPA induced the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) in LPS- activated microglia. Preteatment with the inhibitor of p38 MAPK, SB203580, significantly blocked VPA-induced inhibition of P2X4R and TNF-α mRNA expression in LPS-activated microglia. Thus, given the fact that VPA exerts the effect on the reduction of P2X4R and TNF-α mRNA expression in LPS-activated microglia through the p38 MAPK-dependent signal pathway.
中文摘要 2
英文摘要 4
誌謝 6
目錄 8
表目錄 10
圖目錄 11
縮寫表 12
前言 13
一、中樞神經系統(central nervous system) 13
二、中樞神經系統脊髓之介紹 14
三、微膠細胞在中樞神經系統的角色 15
四、微膠細胞與脊髓損傷的分子機制和組織的修復 16
五、嘌呤受體與微膠細胞活性之關係 17
六、丙戊酸(valproic acid)的簡介 19
實驗目的 23
材料與方法 24
一、材料 24
(一)、細胞培養材料 24
(二)、化學藥品 24
(三)、抗體 25
(四)、試劑組 25
二、方法 26
(一)、大腦初級微膠細胞(primary microglia)細胞培養 26
(二)、細胞毒性分析 (LDH cytotoxic assay) 27
(三)、細胞存活率分析 (cell viability assay) 27
(四)、核酸即時定量分析 (Quantitative Real-Time Polymerase Chain Reaction, Q-PCR) 28
(五)、P2X4R mRNA衰退分析 29
(六) 、西方點墨法(Western blotting) 29
(七)、動物實驗 31
(八)、統計分析 33
結果 34
一、脊髓損傷後微膠細胞P2X4R表現上升 34
二、丙戊酸影響微膠細胞的型態不影響存活率 34
三、丙戊酸抑制微膠細胞P2X4R基因表現 35
四、丙戊酸抑制微膠細胞P2X4R mRNA表現量非透過histone modification 37
五、丙戊酸透過p38 MAPK而降低微膠細胞P2X4R基因表現 38
六、丙戊酸透過p38 MAPK而降低微膠細胞TNF-α基因表現 39
討論 40
一、丙戊酸對微膠細胞活性的影響進而降低P2X4R的表現 40
二、丙戊酸對微膠細胞P2X4R表現的有效作用時間 41
三、VPA促進脊髓組織修復不經抑制HDAC活性的可能性 42
結論 44
參考文獻 45
表一、利用microarray分析,微膠細胞經由LPS處理後,purinergic receptors的表現量 54
表二、利用microarray分析,參與細胞趨化激素之分子性功能中mRNA表現量有變化之列表(mRNA變化量由高較低排名前十項) 55
圖一、脊髓損傷後微膠細胞P2X4R表現上升 56
圖二、丙戊酸不影響LPS活化的微膠細胞型態 57
圖三、丙戊酸不影響LPS活化的微膠細胞型態 58
圖四、丙戊酸不造成毒性且不影響微膠細胞的存活率 59
圖五、丙戊酸抑制微膠細胞的P2X4R mRNA表現 60
圖六、丙戊酸處理的時間長短皆抑制微膠細胞的P2X4R mRNA表現 61
圖七、HDAC抑制劑增加微膠細胞的P2X4R mRNA表現 62
圖八、丙戊酸會影響微膠細胞的P2X4 R mRNA的穩定性 63
圖九、丙戊酸使以LPS活化微膠細胞的p38 MAPK蛋白質磷酸化表現量增加 64
圖十、丙戊酸透過p38 MAPK而降低微膠細胞P2X4R基因表現 65
圖十一、丙戊酸降低微膠細胞TNF-α基因表現 66
圖十二、HDAC抑制劑增加微膠細胞的TNF-α mRNA表現 67
圖十三、丙基戊酸透過p38 MAPK而降低微膠細胞TNF-α基因表現 68

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