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標題: | ENT2在調控脂多糖所誘發神經發炎之角色探討 The role of ENT2 in the modulation of lipopolysaccharide-induced neuroinflammation |
作者: | 李之瑀 Chih-Yu Lee |
指導教授: | 林君榮 Chun-Jung Lin |
關鍵字: | 第二型核?轉運蛋白,神經發炎,腺?, equilibrative nucleoside transporter 2,neuroinflammation,adenosine, |
出版年 : | 2019 |
學位: | 碩士 |
摘要: | 神經發炎是許多腦部相關疾病的共同病徵,而自體抗發炎物質腺苷其胞外濃度的變化已知對於調控發炎的嚴重程度具有一定影響力。其中,第一型及第二型平衡型核苷轉運蛋白 (equilibrative nucleoside transporters, ENTs) 是腦內主要負責調控細胞內外腺苷運輸及恆定的膜蛋白。由於我們的研究發現ENT2於腦部的表現量明顯高於ENT1,因此透過CRISPR-Cas9技術產製出ENT2基因剔除小鼠作為本實驗主要使用的動物模型,嘗試探討ENT2對於由脂多糖所引起的神經發炎所扮演的角色。研究結果發現ENT2基因剔除可以使得因脂多糖所引起細胞激素 (cytokine) 之mRNA表現量增加、星狀膠細胞增生 (astrogliosis)、微膠細胞活化程度提高等發炎反應都獲得顯著緩解。此外,腦部微透析的結果亦顯示相較於littermate小鼠而言,ENT2基因剔除鼠具有較高的胞外腺苷濃度,並會因為多劑脂多糖的刺激產生上升趨勢。綜上所述,我們的研究指出ENT2對於維持腦部胞外腺苷恆定及影響腺苷調控之神經保護機制中佔有很重要的角色。 Neuroinflammation is a common characteristic of many brain related disorders. Adenosine is an endogenous anti-inflammatory agent and its extracellular level in the brain may play an important role in modulating the status of neuroinflammation. The equilibrative nucleoside transporters, ENT1 an ENT2, are the major membrane transporters responsible for cellular uptake of adenosine and the maintenance of extracellular adenosine level in the brain. Given that the expression of ENT2 is higher than that of ENT1 in the brain of mice, ENT2 knockout (KO) mice were established by CRISPR-Cas9 technique and used to clarify the roles of ENT2 in modulating neuroinflammation induced by the treatment of lipopolysaccharide (LPS). The results showed that ENT2 KO significantly ameliorated the LPS-induced neuroinflammation, in terms of the increase of cytokine levels, astrogliosis and microglia activation. The results of in-vivo brain microdialysis study confirmed that the basal level of extracellular adenosine were higher in ENT2 KO mice than that in the littermate controls. Moreover, multiple LPS treatments caused a significant increase in brain adenosine level in ENT2 KO mice, but not in the littermate controls. Taken together, these findings suggest that ENT2 play a crucial role in maintaining extracellular adenosine and adenosine-mediated neuroprotection in LPS-induced neuroinflammation. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78815 |
DOI: | 10.6342/NTU201603665 |
全文授權: | 未授權 |
電子全文公開日期: | 2024-03-11 |
顯示於系所單位: | 藥學系 |
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