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dc.contributorShinn-Zong Linen_US
dc.contributorChun-Rong Chenen_US
dc.contributor.advisorChi-Mei Hsuehen_US
dc.contributor.authorHung, Wan-Tingen_US
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dc.description.abstract中文摘要 瘦素( leptin)是肥胖基因(ob)的產物,分子量為16 kDa的蛋白,主要由脂肪細胞所分泌,透過循環系統對周邊以及腦組織造成不同之影響。它具有調控食慾、能量代謝、內分泌及免疫反應等功能。近期亦有文獻指出Leptin具有保護缺血腸組織的功能,但是對缺血腦組織的保護及作用機轉仍所知有限。因此本論文的研究主軸是評估Leptin對缺血腦組織之保護是透過何種作用機轉,特別針對Leptin對神經細胞及嗜中性白血球的調控做探討,希望將此研究成果用於日後腦缺血之治療及預防上。實驗中,首先將神經細胞置於缺氧、缺糖及缺血清的環境中(GOSD; glucose-oxygen-serum deprivation)培養而後觀察細胞之存活,以及Leptin、Leptin受體(ObR)在GOSD神經細胞中的表現,並外加Leptin於GOSD神經細胞評估其保護性及對STAT3的活化。另外,利用頸動脈結紮(CCAO or common carotid artery occlusion)及中大腦動脈結紮(MCAO or middle cerebral artery occlusion)的方式,建立一個缺血的動物模式,並以外加Leptin於腦部的方式,評估Leptin對缺血腦組織的保護,以及對缺血鼠腦部和脾臟中嗜中性白血球數目及活性的調控。研究結果顯示,Leptin對缺血腦組織具保護性,其保護機轉主要透過提升GOSD神經細胞存活率,修復神經功能及降低缺血腦組織嗜中性白血球的聚集所致。實驗證明在GOSD神經細胞中及缺血組織的梗塞區,皆發現內生性Leptin的表現有明顯上升的趨勢。細胞免疫染色法進一步驗證GOSD神經中ObR的表現量也明顯提高。若外加2uM Leptin到GOSD神經細胞中,細胞中STAT3之表現及細胞之存活率明顯提高,顯示Leptin對GOSD神經細胞具保護性。將Leptin(15ug/kg)直接注射到缺血鼠之大腦延髓腔(CM),大腦皮質區腦梗塞的區域明顯變小,受損的神經功能亦明顯修復,同時梗塞區聚集的嗜中性白血球數目明顯降低,顯示Leptin對缺血腦組織的確具保護性。且此保護機轉明顯和嗜中性白血球受到抑制有關。實驗中更進一步驗證,將自缺血鼠脾臟中嗜中性白血球取出外加Leptin培養,驗證Leptin對缺血鼠脾臟(周邊)嗜中性白血球的直接或間接性調控。發現,腦部外加Leptin可明顯提升脾臟中嗜中性白血球的吞噬能力,嗜中性白血球一旦進入腦部可幫助清除組織殘骸。脾臟中嗜中性白血球的移動力可被腦部的Leptin間接提升,但進入腦部之嗜中性白血球數目明顯受Leptin抑制,顯示Leptin在腦部可透過其它方式,抑制嗜中性白血球的入侵,降低發炎的可能性。另外,Leptin對嗜中性白血球的存活雖具有直接提升的效益,但此時嗜中性白血球釋放NO的活性明顯被抑制,一旦此細胞進入腦部則會降低因NO所導致的腦組織傷害。至此,Leptin對嗜中性白血球活性的調控,似乎均朝向保護缺血腦組織的方向發展,此結果除可進一步驗證Leptin的保護效益及作用機轉外,亦突顯嗜中性白血球對缺血腦組織的影響力,未來在腦缺血的預防或治療上或許可考慮使用Leptin或以短暫剔除嗜中性的方法達到保護腦組織的目的。zh_TW
dc.description.abstractAbstract Leptin is a 16 kDa protein encoded by the obese (ob) gene, synthesized primarily in adipose tissue. It has difference function though binding of Leptin receptor on surrounding and brain tissues. Leptin is involved in regulating feeding, energy metabolism, neuroendicrine and immune function. There is evidence that Leptin can protect intestine from ischemia-induced tissue damage. Reports regarding Leptin-mediated protection of ischemic brain are rare and the mechanism(s) involved are unclear yet. The primary goal of the thesis was therefore to assess the protective mechanism(s) of Leptin in cerebral ischemia. We particularly focus on the effects of Leptin on neurons and neutrophils of the cerebral ischemic rats. In the study, primary neurons isolated from cortex of embryo rat (E18) were exposed to glucose-oxygen-serum deprivation (GOSD) stress, followed by analysis protein expression of Leptin and its receptor (ObR) at various time. Additional Leptin was also added to GOSD neuron to assess its protection of GOSD neuron and effect on STAT3 phosphorylation. In the meantime, a reversible focal ischemia was developed in S.D. rats by subjecting animals to 90min-CCAO plus-MCAO followed by reperfusion for various time. Effects of Leptin on brain infarct and neutrophils in brain and periphery were then evaluated in this ischemic animal model. Our results showed that Leptin can protect ischemic brain by increasing survival of neurons, restoring neurological deficit and preventing brain entrance of neutrophils. Leptin expression levels were increased at brain infarct area and within GOSD neurons. The expression of ObR was also increased in GOSD neuron. Leptin (2uM) supplement enhance the phosphorylation of STAT3 and attenuated GOSD induced neuronal death in vitro. Administration of 15 ug/kg Leptin into the ischemic brain not only reduced the infarct volume, partially restored the neurological function but also decreased the neutrophil infiltration at the infarct area. The Leptin effects on splenic neutrophils were further exammed directly by co-culturing the splenic neutrophil with leptin in vitro or indirectly by viewing the activity changes of splenic neutrophil isolated from ischemic rats with brain injected Leptin. Results showed that brain injection of Leptin not just prevent the brain entrance of neutrophil but also stimulated the phagocytic activity and mobility of splenic neutrophil. These observation indicate leptin may trigger other mechanisms (such as decrease the BBB permeability to prevent the brain infiltration of neutrophil). The release of NO from splenic neutrophils however, were not influenced by Leptin. Co-culturing neutrophil with Leptin in vitro suppressed the mobility of and NO release capability of neutrophil whereas increased the survival of splenic neutrophil in vitro. In overall, Leptin can protect the ischemic brain by promoting the survival of neurons and phagocytotic activity of splenic neutrophil, but preventing the brain entrances and pro-inflammatory activity of neutrophil. These results can further strengthen our knowledge about leptin-mediated brain protection against cerebral ischemia. In addition, leptin supplementation or temporary neutrophil depletion may be therapeutic useful in the future treatment of this disease.en_US
dc.description.tableofcontents目 錄 中文摘要 i 英文摘要 iii 目 錄 v 圖目錄 viii 壹、 前 言 - 1 - 一、 中風 (Stroke) - 1 - 二、 中風與發炎 - 2 - 三、 噬中性白血球 - 3 - 四、 Leptin的功能和調節 - 3 - 五、 Leptin在免疫功能上的調控 - 4 - 六、 Leptin在發炎過程中所扮演的角色 - 5 - 七、 Leptin的接受器和訊號傳遞 - 6 - 八、 ObR在腦部的表現及執行的功能 - 7 - 九、 Leptin在腦缺血所扮演的角色 - 8 - 十、 研究目標 - 9 - 貳、 材料與方法 - 11 - 一、 試劑 - 11 - 二、 神經細胞的培養方法 - 11 - 三、 細胞體外缺血處理( glucose-oxygen-serum deprivation or GOSD) - 12 - 四、 體外缺血神經細胞之Leptin處理 - 12 - 五、 細胞存活率之分析( Trypan Blue Exclusion Assay) - 12 - 六、 細胞免疫染色法( immunocytochemistry) - 12 - (一) 細胞接種 - 13 - (二) 固定細胞 - 13 - (三) 細胞免疫染色法 - 13 - 七、 中風鼠的動物模式 - 14 - (一) 動物 - 14 - (二) 頸動脈結紮及中大腦動脈結紮(CCAO&MCAO) - 14 - 2.1 結紮處理 - 14 - 2.2 再灌流(Re-perfusion) - 14 - 八、 注射ObR-Ab或Leptin到缺血鼠 - 15 - 九、 TTC染色法 - 15 - 十、 免疫組織染色法(immunohistochemistry) - 15 - (一) 組織固定 - 15 - (三) 組織免疫染色法 - 16 - 十一、 Hematoxylin-Eosin 染色 - 17 - 十二、 蛋白質濃度分析 - 17 - (一) 細胞蛋白質萃取 - 17 - (二) 組織蛋白萃取 - 18 - (三) SDS-PAGE製備 - 18 - (四) SDS-PAGE電泳(SDS-Polyacryamide Gel Electrophoresis) - 18 - (五) 蛋白質轉漬(Protein Transfer) - 19 - (六) 西方墨點分析法(Western Blot Assay) - 19 - 十三、 老鼠行為之rotarod(滾輪跑步機)測試 - 19 - 十四、 嗜中性白血球活性分析 - 20 - (一) 脾臟之嗜中性白血球分離法 - 20 - (二) 嗜中性白血球活性-亞硝酸釋放法(Nitrite release assay) - 20 - 十五、 嗜中性白血球之吞噬作用 - 21 - (一) 螢光小球之配置 - 21 - (二) 偵測吞噬作用 - 21 - 十六、 嗜中性白血球之移動能力 - 22 - 十七、 嗜中性白血球之存活率測試 - 22 - 十八、 統計分析 - 22 - 参、結果 - 23 - 一、 體外缺血(GOSD)會誘發神經細胞中Leptin的表現 - 23 - 二、 神經細胞上之ObR的表現明確因GOSD而提升 - 23 - 三、 Leptin可以保護神經細胞抵抗 GOSD的傷害 - 23 - 四、 Leptin會增加GOSD神經細胞中STAT3磷酸化的表現 - 24 - 五、 腦缺血/再灌流 會促使Leptin在梗塞區域大量表現 - 24 - 六、 缺血/再灌流 明顯提升腦組織中p-STAT3及p-ERK的表現量 - 25 - 九、 Leptin可以修復因缺血導致的神經功能受損情形 - 26 - 十、 Leptin減少嗜中性白血球進到缺血鼠腦部的數目 - 26 - 十一、 直接外加Leptin會提升缺血鼠脾臟中嗜中性白血球之存活率 - 26 - 十二、 腦部對外加Leptin,明顯提升缺血鼠脾臟嗜中性白血球之吞噬 能力及移動力 - 27 - 十三、 腦部外加Leptin,對缺血鼠脾臟中嗜中性白血球釋放NO之能力並無影響,但在體外可直接抑制NO之釋放 - 27 - 肆、 討論 - 28 - 參考文獻 - 34 - 圖目錄 圖一、神經細胞中Leptin的蛋白表現明顯因GOSD提升…………………………………-47-. 圖二、神經細胞長鍊和短鍊Leptin受體(ObR-L及ObR-S)的總蛋白表現量不受GOSD之影.響……………………………………………………………………………………….-48- 圖三、神經細胞表面Leptin受體(ObR)的表現明顯因GOSD而提升……………………-49- 圖四、Leptin可保護神經細胞抵抗GOSD造成的傷害……………………………………-50- 圖五、Leptin會增加神經細胞中p-STAT3的表現………………………………………….-51- 圖六、缺血/再灌流 明顯提升腦組織梗塞區(infarct area) Leptin的表現…………………-52- 圖七、缺血/再灌流 明顯提升腦組織梗塞區中p-ERK 及p-STAT3的蛋白表現量............-53- 圖八、ObR 抗體對Leptin作用之干擾並沒有加劇缺血腦組織的受損情形………………-54- 圖九、腹腔外加Leptin無法改善缺血腦組織的栓塞現象………………………………….-55- 圖十、腦部外加Leptin明顯降低缺血腦組織的栓塞現象………………………………….-56- 圖十一、腦部外加Leptin可以修復缺血/再灌流對老鼠神經性功能的傷害 ……………-57- 圖十二、腦部注射Leptin明顯抑制嗜中性白血球在腦梗塞區的數目……………………-58- 圖十三、Leptin在體內對缺血鼠脾臟中嗜中性白血球的存活率不具影響,但在體外可提升存活率……………………………………………………………………………….-59- 圖十四、Leptin在體內明顯提升缺血鼠脾臟中嗜中性白血球的吞噬能力,但在體外不具影響力…………………………………………………………………………………-60- 圖十五、Leptin在體內明顯促進缺血鼠脾臟中嗜中性白血球之移動能力,在體外的影響則不一致……………………………………………………………………………….-61- 圖十六、Leptin在體內對缺血鼠脾臟中嗜中性白血球釋放NO的能力不具影響性,但在體外具抑制性…………………………………………………………………………-62zh_TW
dc.subjectcerebral ischemiaen_US
dc.titleLeptin-mediated protection of ischemic brain: regulation of neutrophil and neuron.en_US
dc.typeThesis and Dissertationzh_TW
item.fulltextno fulltext-
item.openairetypeThesis and Dissertation-
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