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研究生:高品筠
研究生(外文):Pin-yun Kao
論文名稱:顆粒性白血球群落刺激因子可刺激Akt/GSK3β/NFκB的訊息傳遞以抑制內毒素引起之過渡活化的微膠細胞
論文名稱(外文):G-CSF initiates Akt/GSK3β/NFκB signalings in suppressing the enhanced iNOS expression and NO production in LPS-activated BV-2 microglia
指導教授:郭重雄郭重雄引用關係
指導教授(外文):Jon-Son Kuo
學位類別:碩士
校院名稱:慈濟大學
系所名稱:藥理暨毒理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
畢業學年度:96
語文別:英文
論文頁數:44
中文關鍵詞:內毒素一氧化氮誘導型一氧化氮合成��神經發炎顆粒性白血球-群落刺激因子微膠細胞AktGSK3βNFκB
外文關鍵詞:microglialipopolysaccharideNitric oxideInducible nitric oxide synthaseG-CSFNeuroinflammationAktNFκBGSK3β
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神經發炎(neuroinflammation)是造成神經病變及退化的重要成因之一。其中微膠細胞(microglia)過度活化扮演重要角色。微膠細胞活化造成超量的一氧化氮(NO)導致神經細胞的受損及傷亡。顆粒性白血球-群落刺激因子(granulocyte-colony stimulatin factor, G-CSF)是一種神經滋養因子,具神經保護及抗神經發炎的作用。然而在神經發炎中,G-CSF是否調節微膠細胞以達到保護神經細胞的作用尚未知曉。本研究發現在小鼠微膠細胞株BV-2的確有G-CSF的受體存在,暗示G-CSF可修飾微膠細胞的功能。內毒素會活化BV-2,增加誘導型一氧化氮合成�﹛]iNOS)的表現,使一氧化氮產量增加。此BV-2的活化可被G-CSF前處理降低。而G-CSF的前處理,會使磷酸化Akt,磷酸化glycogen synthase kinase 3β (GSK3β),以及細胞質nuclear factor-kappa B (NFκB)的增加。本研究首度證明G-CSF可以透過Akt/GSK3β/NFκB的訊息傳遞以抑制內毒素BV-2刺激的過渡活化。G-CSF在神經退化性疾病中是重要的神經保護藥物。
Microglia activation enhances expression of the inducible NO synthase (iNOS) to over produce nitric oxide (NO), leading to neuronal damage. Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and anti-inflammatory effects. None is known about whether G-CSF may reduce the enhanced iNOS expression and NO production caused by the activated microglia. The investigator for the first time demonstrated G-CSF receptor on BV-2 microglia, indicating G-CSF may modulate function of the microglia. The microglia subjected to stimulation of lipopolysaccharide (LPS) enhanced iNOSmRNA/protein expression and NO production. This effect was suppressed by G-CSF pretreatment. The LPS treatment did not affect Akt expression, but increased p-GSK3β. Furthermore, it decreased cytosolic NFκB at 15 min, but increased at 30 min, 1 hr, and 12 hr. The G-CSF pretreatment caused greater increases in phosphorylated-Akt, phosphorylated-GSK3β, and cytosolic nuclear factor-kappa B (NFκB) at all time points. In conclusion, This is the first investigation demonstrating that G-CSF through activation of Akt/GSK3β and inactivation of NFκB suppresses LPS-induced microglial activation. This novel mechanism may reinforce the neuronally protective effect of G-CSF in neurological diseases.
English Abstract………………………………………………1
Chinese abstract………………………………………………2
Introduction……………………………………………………3-12
Rationale and Hypothesis……………………………………12-13
Purpose…………………………………………………………13
Materials and methods………………………………………13-18
Experimental protocol………………………………………16-17
Results…………………………………………………………18-19
Discussion………………………………………………………20-23
Conclusion……………………………………………………23
References………………………………………………………24-29
Figures…………………………………………………………30-41
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