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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92010
標題: | 為研究於多重神經退化症患者血漿中差異性表現的微小核糖核酸建立之人類體外模型 Establishment of Human In vitro model: Paving Ways to Study Parkinsonism Patient Plasma Related MicroRNAs |
作者: | 呂佳蓁 Chia-Chen Lu |
指導教授: | 林劭品 Shau-Ping Lin |
關鍵字: | 多重神經系統退化症,可誘導之 α-Syn 寡突觸膠細胞株,微核糖核酸,髓鞘相關蛋白,寡突觸膠細胞 α-突觸核蛋白相關疾病, Multiple system atrophy,alphα Synuclein inducible oligodendrocyte progenitor cell line,microRNA,myelin related protein,oligodendrosynucleinopathy, |
出版年 : | 2024 |
學位: | 碩士 |
摘要: | 多重神經系統退化症(MSA)是一種非典型的帕金森氏症(PD),缺乏早期診斷的生物標誌和治療方法。在MSA中,常見的病理標誌是在寡突觸膠質細胞(OL)中α-突觸核蛋白(α-Syn)的異常堆積。寡突觸膠質細胞是中樞神經系統(CNS)中形成髓鞘的神經膠質細胞。目前大多數研究使用囓齒動物細胞或組織作為模型;另外,許多研究使用髓鞘相關基因啟動子來調節人類α-Syn,這只能說明α-Syn對寡突觸膠質細胞發育過程的影響。為了克服這個限制,我們使用人類寡突觸膠質前驅細胞株建立了α-Syn 誘導系統(MO3.13α-Syn),使我們能在特定發育階段進行α-Syn影響的研究。首先,我們利用不同的分化方式以及延長MO3.13的分化時間,以了解其處於何種分化階段,並確定分化的最佳條件。於MO3.13α-Syn中,我們發現誘導α-Syn對分化後的寡突觸膠細胞造成毒性,並對寡突觸膠細胞的成熟和髓鞘形成產生缺陷的潛在性。此外,我們還發現,在誘導α-Syn表現的寡突觸膠細胞中,部分microRNA表達水平的改變重現了MSA患者血漿中的觀察結果。這些microRNA是透過我們獨特的數據分析方式成功篩選出來,能區分MSA患者與健康對照組,表明誘導α-Syn表現的寡突觸膠細胞中miRNA與MSA血漿中miRNA可能的關連性。分化中的寡突觸膠細胞對異常α-Syn表達之敏感性顯示了其作為突觸核蛋白疾病藥物標靶快速篩選平台之潛力,而在過度表達α-Syn的寡突觸膠細胞中,下降的髓鞘相關基因和miRNA的變化也有機會作為檢驗藥物標靶的指標。 總體而言,我們的人類體外模型具有作為迅速篩選MSA寡突觸膠細胞α-突觸核蛋白疾病的標靶藥物之平台的潛力。 Multiple system atrophy, an atypical Parkinson’s disease (PD), is lacking biomarkers for early diagnosis and disease-modifying therapies. One well-known pathological hall mark of MSA is that alphα-Synuclein (α-Syn) aberrantly accumulates in oligodendrocytes (OL), an essential neural glial cell for neuron myelination in the central nervous system (CNS). Most studies focus on rodent models for α-Syn formation, but a crucial need exists for a human in vitro model due to significant cell environment impacts. Furthermore, many investigations use myelin gene promoters to regulate transgenic human α-Syn, implying effects on oligodendrocytes during development. To overcome these limitation, we established an inducible system for α-Syn using a human oligodendrocyte progenitor cell line (MO3.13α-Syn), allowing targeted exploration at specific developmental stages. Initially, we utilized various protocols and prolonged the differentiation duration of MO3.13 to evaluate their status over extended periods and determine the optimal conditions for differentiation. Within MO3.13α-Syn, we demonstrated α-Syn induced cytotoxicity in differentiating oligodendrocytes and down-regulated pathways related to myelin, which might implicate defects on maturation and myelination in human oligodendrocytes overexpressing α-Syn. Furthermore, we revealed that the alteration in the expression level of some microRNAs in differentiating oligodendrocytes overexpressing α-Syn reproduced the observation in the plasma of MSA patients, which were successfully selected via our unique data analytic scheme to robustly differentiate MSA patients from healthy control (HC). The susceptibility of oligodendrocyte differentiation stages to abnormal α-Syn expression implies its potential as a swift screening tool for drug targets in MSA-related oligodendrosynucleinopathy. The suppressed myelin pathways and altered microRNA expression in differentiating oligodendrocytes with α-Syn overexpression suggest their potential as indicators for drug targets. In summary, our model holds potential as an expedient platform for screening drug targets for MSA-associated oligodendrosynucleinopathy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92010 |
DOI: | 10.6342/NTU202400727 |
全文授權: | 同意授權(限校園內公開) |
電子全文公開日期: | 2029-02-17 |
顯示於系所單位: | 生物科技研究所 |
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