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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 劉興華 | |
dc.contributor.author | Ya-An Chang | en |
dc.contributor.author | 張雅銨 | zh_TW |
dc.date.accessioned | 2021-06-07T18:03:31Z | - |
dc.date.copyright | 2012-09-19 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-07-30 | |
dc.identifier.citation | Adhami F, Liao G, Morozov YM, Schloemer A, Schmithorst VJ, Lorenz JN, Dunn RS, Vorhees CV, Wills-Karp M, Degen JL, Davis RJ, Mizushima N, Rakic P, Dardzinski BJ, Holland SK, Sharp FR, Kuan CY (2006) Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. The American journal of pathology 169: 566-583
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16165 | - |
dc.description.abstract | 根據世界衛生組織統計,中風及腦血管相關疾病造成的死亡人數高居世界十大死因中的第二位,而在台灣,每年有數萬人死於中風疾病。超過85%腦中風患者屬於缺血性中風,患者接受抗血栓藥物或手術移除阻塞血塊後,腦部組織會承受缺氧/再灌流(hypoxia/reperfusion)傷害,文獻指出,缺氧再灌流除了誘發內質網壓力、過氧化物生成外,在腦部尤其會引起離子調控失常而產生毒性反應。腦部由多種不同形態的細胞組成,微膠細胞(microglial cells)為中樞神經系統的巨噬細胞,遭受刺激後可迅速活化,是腦部一重要的非特異性免疫細胞;神經細胞負責傳遞訊息,然而兩者間的調控則尚未清楚。本篇研究使用小鼠微膠細胞株(BV-2)模擬腦部受到缺氧在灌流傷害後的免疫細胞的活化情形,並和神經母細胞瘤細胞株(IMR-32),初代神經細胞(primary neuronal cells)及小鼠腦部體內實驗相互對照。細胞株均先換為未含血清的培養液並移至低氧培養箱(O2≦1%)培養六個小時,而後加入10%血清並移往一般培養箱培養不同時間點,小鼠則施以腦部暫時性動脈拴塞及再灌流手術以模擬再灌流環境。MTT assay及流氏細胞儀顯示微膠細胞株中,再灌流環境會隨著時間增加使細胞凋亡增加,西方墨點法發現Akt蛋白在缺氧期間大量磷酸化、自噬作用大量增加;再灌流時期Akt磷酸化則會下降、自蝕作用減少,PARP和caspase-3等死亡標記蛋白在灌流後期有明顯表現;相同處理條件下的神經母系胞瘤細胞,初代神經細胞和小鼠腦部則發現,無論在缺氧或再灌流時期Akt磷酸化均持續表現,後期細胞凋亡情形不明顯。進一步研究微膠細胞訊息傳遞路徑,發現可經由Akt磷酸化活化mTOR,進而抑制自噬作用,接著使用shRNA剔除ATG5基因表現以抑制自噬作用,發現抑制自噬作用同時可降低caspase-3表現,推測自噬作用參與微膠細胞的死亡路徑。接著使用抗氧化劑--兒茶素,發現兒茶素可抑制過氧化物的生成,增加Akt和mTOR磷酸化,抑制自噬作用,進而降低細胞凋亡。本實驗探討遭受缺氧再灌流傷害時微膠細胞的變化,並和神經母細胞瘤,初代神經細胞和小鼠腦部實驗比較,發現微膠細胞對缺氧再灌流傷害較為敏感,並可透過Akt和mTOR磷酸化抑制自噬作用以保護細胞;抗氧化劑兒茶素也可經由活化Akt-mTOR路徑而抑制自噬作用,以降低微膠細胞受到的缺氧再灌流傷害。本篇體外實驗發現腦部微膠細胞可藉由Akt磷酸化訊息傳遞抑制自噬作用造成的傷害,抗氧化劑也可經由上述路徑以達到保護微膠細胞的功效。 | zh_TW |
dc.description.abstract | According to World Health Organization, stroke and cardiovascular disease are the second leading causes of death worldwide. Stroke occurs because of interruption of blood flow due to thrombosis, known as hypoxia/ischemia injury. Patients with stroke will experience sudden paralysis, loss of vision or death. Hypoxia/reperfusion (H/R) injury occurs when thrombosis is removed. Several researches have stated that H/R injury can cause damage to brain cells through ATP depletion, reactive oxygen species, inflammation or apoptosis. The aim of this research is to investigate the mechanism of H/R injury in different types of brain cells. Microglial cells are macrophages in the Central Nerve System, and they can be activated immediately under stress pressure. The neuronal cell is responsible to transmit the signal. However, the mechanism of H/R injury in different cells is still unclear. Therefore, in order to create H/R injury, microglial cells (BV-2), neuronal cells (IMR-32) and primary neuronal cells were treated with serum-free medium for 6 hours under hypoxia condition, then transferred to normoxia chamber and adding serum back. The mice were treated with middle cerebral artery occlusion and reperfusion. MTT assay and caspase-3 expression showed H/R caused more severe injury in BV-2 than IMR-32 and primary neuronal cells. Western blots showed LC3-II, an autophagy marker, significantly increased during hypoxia period and decreased in reperfusion period in BV-2. On the other hand, H/R injury induced slightly LC3-II signal in IMR-32, primary neuronal cells and in vivo at the beginning of H/R treatment. We also showed that hypoxia injury can cause the phosphorylation of Akt and decreased in reperfusion period in BV-2. With the same condition, there is a continuous phosphorylation of Akt in IMR-32, primary neuronal cells and in vivo in mice brain. To further confirm the modulation of Akt and autophagy in BV-2. We found that suppression of Akt by LY294002, a PI3K inhibitor, could decrease the mammalian target of rapamycin (mTOR) expression but increase autophagy in BV-2. Next, inhibition of mTOR by rapamycin could increase the autophagy, too. Meanwhile, knock down ATG5 leaded to decreased autophagy and expression of caspase-3. Taken together, the expression of Akt leaded to mTOR phosphotylation and suppression of autophagy, which plays a protective role in BV-2 by H/R injury. Moreover, we investigated the mechanism of the antioxidant, catechin hydrate, in BV-2. We found the catechin hydrate could up-regulate the phosphorylation of Akt and mTOR, decrease induction of autophagy and protect cells from apoptosis. In conclusion, the autophagy was regulated by Akt-mTOR-autophagy in BV-2. Catechin hydrate could attenuate the H/R injury in BV-2 by decrease the Akt-mTOR-regulated autophagy. Our data suggested the autophagy regulated by Akt-mTOR signal is involved in the microglia cells death. Inhibition of autophagy by catechin hydrate could provide a new opinion for H/R treatment in microglial cells. | en |
dc.description.provenance | Made available in DSpace on 2021-06-07T18:03:31Z (GMT). No. of bitstreams: 1 ntu-101-R99447006-1.pdf: 1836324 bytes, checksum: a4b1957741341934b2d937412b5a15d0 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 中文摘要……………………………………………………………….…...………... ..iv
ABSTRACT…………………………………………………………...………...……..vi ABBREVIATIONS……………………………………………………….……………ix CHAPTER I INTRODUCTION…………………………………..……………….1-11 1.1 Stroke.....………………………………………………....……………………..1 1.2 Brain………………………………………………………….......…………….3 1-3 Autophagy……………………………………………………...........…………6 1-4 Akt……………………………………………………………......…………….8 1-5 Catechin hydrate…………………………………………………...................10 Aims of the thesis…….………………………………………………..............….11 CHAPTER II MATERIALS AND METHODS……………………….......…….12-18 CHAPTER III RESULTS…………………………………………….…....……...19-25 Figure 1.Effects of hypoxia-reperfusion injury on different types of brain cells……....19 Figure 2. Effects of hypoxia-reperfusion injury on neonatal neuronal cell in vitro and mice brain in vivo…..……………………………………………...………...19 Figure 3. Apoptosis and necrosis were involved in BV-2 death after H/R injury…..….20 Figure 4.Induction of autophagy in brain cells by H/R treatment……....…...…………20 Figure 5.Akt phosphorylation is activated in brain cells by H/R treatment.…...…...….21 Figure 6.H/R increased the generation of reactive oxygen species……..………...……21 Figure 7.H/R increased the phsphorylation of Akt and mTOR but decreased the induction of autophagy in BV-2…………………………………….………...22 Figure 8.Autophagy is involved in BV-2 death by H/R treatment……………...……...22 Figure 9.Akt positively regulates the phosphorylation of mTOR and inhibit the induction of autophagy in BV-2 by H/R treatment…………………...………23 Figure 10.Inhibition of mTOR could activate autophagy……………….……………...23 Figure 11.Catechin hydrate increased the phosphorylation of Akt and mTOR and decreased the induction of autophagy in BV-2 by H/R treatment…..……......24 Figure 12.Catechin hydrate protected BV-2 from apoptosis by H/R treatment…….….25 CHAPTER IV DISCUSSIONS………………………………………...…............26-30 CHAPTER V CONCLUSION……………………………………………………......31 REFERENCES……………………………………………………..……...………32-42 FIGURES………………………………………………………………..…………43-65 | |
dc.language.iso | en | |
dc.title | 微膠細胞遭受缺氧再灌流傷害後之機轉 | zh_TW |
dc.title | The Mechanism of Hypoxia/Reperfusion-Induced Injury in Microglial Cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蕭水銀,楊榮森,姜至剛,陳敞牧 | |
dc.subject.keyword | 缺氧再灌流,微膠細胞,Akt,自噬作用,兒茶素, | zh_TW |
dc.subject.keyword | hypoxia/reperfusion,microglial cells,Akt,mammalian target of rapamycin,autophagy,catechin hydrate, | en |
dc.relation.page | 65 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2012-07-31 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
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