2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643460摘要：DNA 拓樸異構酶參與 DNA 拓撲狀態的調控，維持細胞內基因體 DNA 的正常作用。他們參與在 DNA 複製、轉錄、染色體聚集、和新複製的染色體分離，因此他們對細胞生長和組織發育是必須的。DNA 拓樸異構酶目前是許多抗癌、抗細菌、抗真菌、和抗原蟲藥物的標的物。梨形鞭毛蟲是一種單細胞的腸道病原，寄生在小腸而引起腹瀉疾病，每年全世界約有 2.8 億人被感染。梨形鞭毛蟲也是造成感染後腸燥症的原因之ㄧ。類似於痢疾阿米巴和其他寄生於腸道之原蟲，其生活史中的重要目的是要分化成囊體，以存活於體外並傳播疾病。Metronidazole 常被用來治療梨形鞭毛蟲及原蟲感染，但是其抗藥性及副作用問題，造成其使用效果不佳。梨形鞭毛蟲具有幾個與其他真核生物不同的 DNA 拓樸異構酶，可成為抗原蟲藥物的標的物，但目前對於其功能和特性仍所知甚少。我們想知道 DNA 拓樸異構酶在形成囊體時是否扮演任何角色。我們之前的研究發現DNA拓樸異構酶 II可能參與梨形鞭毛蟲在分化形成囊體時增加囊壁蛋白質基因之表現(Lin et al., 2013)。此計劃我們將以生化、細胞學及分子方法來研究可能的 DNA拓樸異構酶參與梨形鞭毛囊體化或細胞生長之功能，我們也將針對 DNA 拓樸異構酶發展抗梨形鞭毛蟲藥物，我們將測試 DNA 拓樸異構酶的抑制劑的抗梨形鞭毛蟲作用，了解 DNA 拓樸異構酶的特性，也了解詳細的殺蟲機制，這將有助於我們發展更佳的治療梨形鞭毛蟲及其他原蟲感染的藥物。 <br> Abstract: DNA topoisomerases are responsible for maintaining normal topology of genomic DNA. They are necessary for cell growth or tissue development as they are involved in DNA replication, transcription, chromosome condensation, and segregation of newly replicated chromosomes. They are valuable targets of anti-cancer, anti-bacterial, anti-fungal, and anti-protozoa drugs. Giardia lamblia is a unicellular intestinal pathogen that parasitizes the human small intestine to cause diarrhea diseases worldwide with an estimated 280 million cases yearly. It is a potential cause of post-infectious irritable bowel syndrome. Like Entamoeba histolytica and other intestinal protozoan pathogens, G. lamblia undergoes differentiation from a trophozoite form into a cyst form that is essential for disease transmission in the life cycle. Metronidazole has been used often in the treatment of Giardia infection, but resistence and side effect limits its use. G. lamblia possesses several DNA topoisomerases that are different from the mammalian topoisomerases. They could be novel drug targets, but little is known of their characters and functions. We tried to understand the role of topoisomerases in Giardia differentiation into cysts. In our previous study, we found that DNA topoisomerase II may be involved in up-regulation of cyst wall protein gene expression during Giardia differentiation into cysts (Lin et al., 2013). In this project, we will characterize the putative DNA topoisomerases to know their role in Giardia encystation or cell growth using biochemical, cell biological, and molecular approaches. We will also focus on these DNA topoisomerases to find a better treatment of giardiasis. We will test various DNA topoisomerase inhibitors to see if they have anti-Giardia effect. We will characterize giardial DNA topoisomerses and find detail mechanisms of the anti-Giardia effect of the effective topoisomerase inhibitors. This study will provide therapeutic perspectives in Giardia and other important intestinal protozoan pathogens.DNA拓樸異構酶轉錄治療用藥囊體囊壁蛋白梨形鞭毛蟲DNA topoisomerasetranscriptiontheraputic drugcystcyst wall proteinGiardia