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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18976
標題: | 以合成的邏輯匣串聯應用至區別化抗分裂之癌症治療 A Cascade of Synthetic Logic Gates for Differentiated Anti-mitotic Cancer Therapy |
作者: | Bo-Han Lian 連柏翰 |
指導教授: | 黃筱鈞 |
關鍵字: | 癌症,抗分裂,基因治療,合成生物學,核糖核酸干擾, cancer,anti-mitotic,gene therapy,synthetic biology,RNA interference, |
出版年 : | 2016 |
學位: | 碩士 |
摘要: | 化學治療是一種常規的癌症療法,傳統的化學治療藥物對分裂中的細胞具有細胞毒性,透過干擾有絲分裂而達成目的,但其缺乏特定標的並時常產生副作用及治療失敗。骨髓抑制(myelosuppression)是抗分裂化學治療的副作用之一,由骨髓內分裂中的造血幹細胞受到破壞所引起;當骨髓抑制嚴重時,可能會導致嗜中性球低下(neutropenia)並時常伴隨著感染,這將會威脅病患的性命。使用基因治療成為克服此副作用的替代方案:我們使用合成生物學的方式,建立了一個對增生中的腫瘤細胞有細胞毒性並對造血幹細胞無害的合成基因線路;此線路以核糖核酸干擾(RNA interference, RNAi)和四環素控制的表現系統(tetracycline-controllable expression system)為基礎,能偵測到來自個別細胞中細胞週期素B1啟動子(cyclin B1 promoter)和miR-142微型核醣核酸結合位點(microRNA binding site,MBS)的訊息並做出反應。所有本線路使用的元件都以螢光蛋白做為報導基因確認其性能,之後串聯至具有優化後的反饋/前饋迴圈的邏輯匣層內。我們展示了一個合成的邏輯基因線路,在體外實驗中標定並殺死增生中的腫瘤細胞。本研究提供了一個有潛力的策略作為癌症基因治療之用。 Chemotherapy is a conventional treatment for cancer. Traditional chemotherapeutic agents are cytotoxic to dividing cells by means of interfering with mitosis but without specific targeting and often cause side effects and frequent failures. Myelosuppression due to destruction of dividing hematopoietic stem cells (HSCs) in bone marrow is one of the side effects for anti-mitotic chemotherapy. When myelosuppression is severe, it may lead to neutropenia and often company with infections that will threaten patient’s life. An alternative way to overcome this side effect is using gene therapy. With a “synthetic biology” approach, we construct a synthetic genetic circuit that cytotoxic to proliferating tumor cells and spare hematopoietic stem cells. The circuit based on RNA interference (RNAi) and tetracycline-controllable expression system is able to detect and respond to cellular information from cyclin B1 promoter and miR-142 microRNA binding site (MBS) in individual cells. All units of circuit were validated its performance by using fluorescence protein as reporter and then cascaded into layers of logic gates with optimizing feedback/feed-forward loops. Here we present a synthetic logic genetic circuit targeting and killing proliferating tumor cells in vitro. This study provides a potential strategy for cancer gene therapy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18976 |
DOI: | 10.6342/NTU201603254 |
全文授權: | 未授權 |
顯示於系所單位: | 分子與細胞生物學研究所 |
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