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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 符文美(Wen-Mei Fu) | |
dc.contributor.author | Chia-Shi Chang | en |
dc.contributor.author | 張家僖 | zh_TW |
dc.date.accessioned | 2021-06-13T02:10:00Z | - |
dc.date.available | 2012-07-10 | |
dc.date.copyright | 2007-07-10 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-06-27 | |
dc.identifier.citation | Ahmad I, Lin SH, Chong ZZ, Kang J, Maiese K (2001) Erythropoietin :a principal modulator of ischemic cerebrovascular endothelial cell programmed cell death Soc Neurosci Abstr 31:394
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30605 | - |
dc.description.abstract | 近來陸續有報告顯示,紅血球生成素(EPO)在細胞或組織缺氧情況之下扮演神經保護的角色。然而其上游調控機轉尚未明確。而AMP-activated protein kinase(AMPK)對於能量的代謝與調控也扮演重要的角色。在組織缺氧的情況之下,AMPK的磷酸化增加,進而影響到下游的基因調控,幫助細胞調節能量的代謝與平衡。AMPK的catalytic subunit (α subunit)有兩種isoforms, 分別為α1及α2, 越來越多的報告顯示α1及α2扮演不同的調控功能。
我們發現在SH-SY5Y細胞株中,EPO在氧化壓力之下會被活化,並且受到AMPK的調控。利用氯化鈷(CoCl2)來模擬細胞缺氧的情況之下,發現除了AMPK的磷酸化增加,HIF-1α及EPO的蛋白表現量都增加。在細胞缺氧情況下,利用藥理及分生技術抑制AMPK的活性後,則HIF-1α及EPO的蛋白量也受到抑制。我們更進一步分別抑制AMPK α1及α2 isoforms ,發現AMPK α2 isoform 在此細胞中對於氧化壓力下引發的HIF-1α及EPO扮演較重要的調控角色。在利用AICAR活化AMPK後,不經氧化壓力,就能夠引發HIF-1α及EPO的蛋白表現。 另外,我們發現在細胞缺氧的情況下,調控glucose代謝的Glucose Transporter 1(GLUT1)也會增加。且受到AMPK的調控。在細胞缺氧情況下,無論利用藥理或分生技術來抑制AMPK的活性,都能達到抑制GLUT1蛋白表現的效果。 我們也發現,抑制AMPK的活性加強MPP+所引發的神經毒性。SH-SY5Y是神經母細胞瘤的細胞株,具有多巴胺神經的特徵,對於MPP+所引發的氧化壓力具有敏感性。在MPP+ 處理下,AMPK的磷酸化增加,同時引發HIF-1α及EPO的蛋白表現量。利用compound C抑制AMPK的活性後,發現在MPP+處理下引發的HIF-1α及EPO蛋白表現也被抑制。 綜合以上結果顯示,在SH-SY5Y神經細胞株中,無論在CoCl2或MPP+引發的氧化壓力下,EPO的合成都會增加,並且是透過AMPK的活化。因此本論文顯示,在氧化壓力下EPO的神經保護角色,與AMPK的活化有關。 | zh_TW |
dc.description.abstract | EPO has been recently proved as a neuroprotective agent both in vivo and in vitro under hypoxia-ischemic models. However, the mechanism for the upregulation of EPO gene expression remained unclear. AMP-activated protein kinase (AMPK) functions as an energy sensor to provide metabolic adaptation under the ATP-deprived conditions such as hypoxia. There are two distinct catalytic isoforms-AMPKα1 and AMPKα2. It is becoming clear that AMPKα1 and AMPKα2 have distinct functions. In our study, we considered that EPO may be activated under oxidative stress via an AMPK-dependent pathway in human neuroblastoma cells. We demonstrated that chemical hypoxia can induce phosphorylation of AMPK in human neuroblastoma cell line SH-SY5Y, and its activation preceded the increase of HIF-1α expression. Western blot analysis revealed that blockade of AMPK activity by pharmacological agent or by molecular approach attenuated HIF-1α and EPO expression. In addition, by separate inhibition of AMPKα1 and AMPKα2 isoforms by using respective dominant mutant, it was found that AMPKα2 subunit was more important in SH-SY5Y cells for the activation of HIF-1α and EPO under hypoxia. The AMPK chemical activator, AICAR, effectively increased the protein levels of HIF-1α and EPO. It was also found that under chemical hypoxia, the protein level of GLUT1 increased. Inhibition of AMPK activity by pharmacological agent or by molecular approach also antagonized the increasing effect of hypoxia on GLUT1.
It was also found that suppression of levels of AMPK α1 or α2 isoforms enhanced neuronal death induced by MPP+, which was evaluated by MTT reaction and Hoechst staining. Under the MPP+-induced oxidative stresses, the protein levels of pAMPK, HIF-1α and EPO were all elevated. Compound C, the chemical inhibitor of AMPK, inhibited the activation of HIF-1α and EPO. In conclusion, these data suggest that AMPK may play a critical role on the induction of EPO under oxidative stress induced by chemical hypoxia or MPP+. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T02:10:00Z (GMT). No. of bitstreams: 1 ntu-96-R94443016-1.pdf: 4630611 bytes, checksum: 42a48786a36f790cc86eb35c4ed1806d (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | 縮寫表……………………………………………………………………1
英文摘要…………………………………………………………………3 中文摘要…………………………………………………………………5 緒論………………………………………………………………………7 實驗材料與方法……………………………………………………….23 結果…………………………………………………………………….29 討論與結論…………………………………………………………….39 圖表…………………………………………………………………….45 參考文獻………………………………………………………………63 | |
dc.language.iso | zh-TW | |
dc.title | AMPK對於神經細胞於低氧及MPP+下引發之EPO的調控作用 | zh_TW |
dc.title | Roles of AMP-activated protein kinase in the chemical hypoxia and MPP+–induced expression of EPO in neuroblastoma cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 95-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林琬琬(Wan-Wan Lin),楊偉勛(Wei-Shiung Yang),楊春茂(Chuen-Mao Yang),陶寶綠(Pao-Luh Tao) | |
dc.subject.keyword | AMPK,低氧,MPP+,EPO, | zh_TW |
dc.subject.keyword | AMPK,hypoxia,MPP+,EPO, | en |
dc.relation.page | 71 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-06-27 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
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