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研究生:洪葦苓
論文名稱:第八型脊髓小腦運動失調症:CTG三核重複的遺傳分析與細胞模式研究
論文名稱(外文):Spinocerebellar ataxia type:genetic analysis of CTG trinucleotide repeat and a cell model study
指導教授:李銘亮
學位類別:碩士
校院名稱:國立臺灣師範大學
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:74
中文關鍵詞:脊髓小腦運動失調症三核重複擴增
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脊髓小腦運動失調症(spinocerebellar ataxia;SCA),為一群異質性的退化性神經疾病,大部分起因於三核重複擴增,患者在小腦、腦幹、脊髓及周邊神經系統等出現漸進式的退化。臨床上SCA不易分類,在多種相關的致病基因被分離後,分子檢測的建立及致病機轉的研究,有助於我們對這群疾病的了解。SCA8和致病基因3'端非轉譯區的CTG三核擴增相關,除家族性及偶發性的運動失調患者外,在阿茲海默氏症(AD)、精神疾病症、帕金森氏症(PD)及其他類型之SCA患者中,甚至於極少數的正常人中,亦可見到異常的CTG三核擴增(68 ~ 800個)。本研究首先建立台灣正常人及上述退化性神經疾病患者,其SCA8基因CTG重複之遺傳資料庫,結果發現有5個擴增的allele,分別來自1個AD患者、3個PD患者與1個SCA3患者。擴增之allele經定序分析顯示包含63 ~ 93個三核重複。另一方面也構築含有不同CTG重複(0, 23, 88, 157個)的SCA8 cDNA於表現載體上,轉移至人類胚胎腎細胞(HEK-293)或老鼠胚胎癌細胞(P19),來研究SCA8可能之致病機轉。結果發現包含0個CTG重複之SCA8基因表現最好,當CTG重複23-157次時,SCA8基因的表現量下降,但下降程度不隨CTG擴增而有明顯差異,且RT-PCR分析顯示SCA8 mRNA在細胞核、質的分布情形與穩定性均不受CTG重複次數影響。和第一型肌強直萎縮症(myotonic dystrophy type 1;DM1)一樣,擴增之SCA8 RNA (CTG重複88或157個)在核內會形成RNA foci。而在SCA8和TBP cDNA或(CAG)36之共轉實驗中,也發現SCA8對TBP RNA或(CAG)36 RNA有類似antisense RNA之作用。上述結果可幫助我們初步了解SCA8表現時其RNA可能造成之效應。
目錄………………...……………………………………………………..I
中文摘要………...…………………………………………………..….IV
英文摘要………………………...………………………………………V
圖表次…………………………………………………………...…….VII
壹、緒論
一、脊髓小腦運動失調症(SCA)……………………………………1二、第八型脊髓小腦運動失調症(SCA8)…………………………..2
三、SCA8基因和KLHL1基因………………………….………….5
四、肌強直萎縮症第一型(DM1)……………………………………6五、DM1之致病假說
(一) DNA層次………………………………..……………….7
(二) RNA層次………………………………………………....8
六、研究動機與目的………………………………………………..9
貳、研究材料與方法
一、血液樣品來源……………………………………....................11
二、基因組DNA的萃取…………...................................................11
三、聚合酵素連鎖反應(PCR)…………………………….........….12
四、基因型分析(Genotyping Analysis)……………………..….….12
五、自洋菜膠中純化DNA片段…………………………...............12
六、接合反應(Ligation)……………………………...………….…13
七、轉形勝任細胞(Competent cell)之製備…………………….....13
八、細菌的轉形作用(Transformation)...…………………………..14
九、質體(Plasmid) DNA的小量製備…………………….…..……15
十、DNA定序(Sequencing)………………………….………..…...15
十一、質體(Plasmid) DNA的大量製備…………….…………..…16
十二、SCA8 cDNA重組質體之構築……………………..….……17
十三、SCA8-ORF3 cDNA重組質體之構築………………..…….18
十四、TBP-cDNA與36Q-cDNA重組質體之構築……..….……..18
十五、SCA8-CTGn質體轉移作用(Transfection)……….…….…...19
十六、TBP或36Q質體與SCA8質體共轉移作用………………..19
十七、流式細胞儀分析(FACS)………...……..…………………...20
十八、細胞之total RNA萃取………………..…………………….20
十九、細胞核、質之RNA萃取…………………....……………….21
二十、細胞RNA之穩定性(stability)分析……………….……..….21
二十一、RT-PCR ………………………………...…………..…….22
二十二、RNA-FISH (RNA-fluorescence in situ hybridization)…...22
參、結果
一、建立台灣不同族群SCA8基因CTG重複之遺傳資料庫….....24
二、研究SCA8基因CTG擴增所造成的可能效應
(一) FACS分析CTG重複擴增對SCA8 RNA表現之影響....24
(二) RT-PCR分析CTG重複擴增對SCA8 RNA表現之影....25
(三) CTG重複擴增與SCA8 RNA foci形成…………………26
(四) SCA8 CTG重複擴增對共轉之TBP RNA的影響…..…27
(五) SCA8 CTG重複擴增對共轉之36Q RNA的影響…..….28
肆、討論
一、建立台灣不同族群SCA8基因CTG重複之遺傳資料庫..…..29
二、研究SCA8基因CTG擴增所造成的可能效應
(一) CTG重複擴增對SCA8 RNA表現之影響………..……29
(二) CTG重複擴增與SCA8 RNA foci形成………………...31
(三) CTG重複擴增對(CAG)n RNA之反義效應………….....32
(四) SCA8完整的ORF3可增強對(CAG)n RNA反義效應.…33
三、未來研究方向
(一)改善重組質體轉移細胞之效率………………..…..……34
(二) SCA8 RNA對TBP RNA或36Q RNA之影響…………35
(三) SCA8表現與細胞凋亡之關聯…………………….……35
(四) SCA8治療層面之細胞模式研究…………..…………..36
伍、參考文獻 ………………………………………………………..…37
陸、附錄圖表……………………...………………………………….....50
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