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研究生:鄭自勝
研究生(外文):Zih-Sheng Cheng
論文名稱:藉由慢病毒載體傳遞galectin-1基因及galectin-3shRNA治療由膠原蛋白所誘導之大鼠關節炎
論文名稱(外文):Delivery of galectin-1 gene and galectin-3 shRNA by lentiviral vector for the treatment of collagen-induced arthritis in rats
指導教授:王崇任蕭璦莉
指導教授(外文):Chrong-Reen WangAi-Li Shiau
學位類別:碩士
校院名稱:國立成功大學
系所名稱:微生物暨免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:67
中文關鍵詞:類風濕性關節炎慢病毒
外文關鍵詞:Rheumatoid arthritislentivirusgalectin-1galectin-3
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類風濕性關節炎是一種關節慢性發炎的疾病,特徵為免疫細胞,包括淋巴細胞、巨噬細胞等浸潤到關節中,伴隨著滑液膜細胞活化、增殖,這些細胞產生大量許多分解性酵素,及Th1細胞激素刺激巨噬細胞等分化為蝕骨細胞,導致軟骨與硬骨被侵蝕破壞。Galectin是一群數目成長中的β半乳糖結合凝集蛋白,其中Galectin-1 (Gal-1)可以引起活化的T淋巴細胞凋亡,並抑制T淋巴細胞產生第二型白介素與巨噬細胞產生腫瘤壞死因子α、干擾素γ;家族中的另一個成員,Galentin-3 (Gal-3)則是淋巴細胞、巨噬細胞、中性白血球的化趨物質,除此之外,Gal-3會抑制T細胞凋亡、促進血管新生,且在類風濕性關節炎病人的關節中被大量表現。在本研究中我們假設透過增加Gal-1表現與抑制Gal-3表現或許能夠改善關節炎的發生與病程,我們篩選出能夠有效抑制Gal-3表現的RNA干擾素,並將Gal-1的表現基因與Gal-3的RNA干擾素分別建構於假型外套膜慢病毒載體中,治療由第二型膠原蛋白引起的大鼠關節炎,研究結果顯示我們建構的慢病毒能有效的使Gal-1過量表現,也有效降低Gal-3的表現,並且相對於給予食鹽水或是表現GFP的對照病毒,給予Gal-1基因或是Gal-3 RNA干擾素的大鼠都在臨床症狀有顯著改善,我們也經由病理學評估與X光攝影評估確認療效,因此Gal-1表現增加或抑制Gal-3表現能改善大鼠關節炎,總而言之,希望我們的研究能夠對於Gal-1與Gal-3在類風濕性關節炎中扮演的角色提供一些線索,並且對治療類風濕性關節炎能有新方向的療法。
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by blood-derived cells, such as macrophages and lymphocytes, infiltrating into joints, and in conjunction with activated synovial cells, production of inflammatory and T helper 1 (Th1) cytokines together with degradative enzymes that progressively lead to the destruction of cartilage and bone. Galectins are a growing family of β-galactoside-binding animal lectins. Galectin-1 (Gal-1) can induce apoptosis of activated but not resting human T cells as well as suppress Tumor necrosis factor α (TNF-α) and Interferon γ (IFN-γ) production by macrophages and Interleukin 2 (IL-2) production by T cells. In contrast to Gal-1, galectin-3 (Gal-3) is chemotactic for lymphocytes, macrophages, and neutrophils. Furthermore, Gal-3 promotes angiogenesis and serves as an inhibitor of T cell apoptosis, and is expressed in the synovial tissue of patients with RA, particularly at sites of joint destruction. In this study, we investigated whether increase of Gal-1 gene expression and reduction of Gal-3 gene expression may be beneficial in ameliorating arthritis onset and progression. We screened efficient short-hairpin RNA (shGal-3) to knockdown rat Gal-3 gene expression by the Gal-3 fusion with eGFP. We generated two VSV-G pseudotyped lentiviral vectors expressing Gal-1 (Lt.Gal-1) and shGal-3 (Lt.shGal-3) for gene therapy in the rat model of collagen-induced arthritis (CIA). Our results demonstrated that Lt.Gal-1 and Lt-shGal-3 efficiently increased Gal-1 and knocked down Gal-3 gene expression. We also administered Lt.Gal-1, Lt.shGal-3, or the control virus, Lt.GFP, to CIA rats to evaluate their therapeutic efficacy. Furthermore, histological and radiological analyses of the rat ankle were evaluated. We found that clinical symptoms and histological scores were ameliorated when Gal-1 expression was increased or Gal-3 was reduced. Taken together, this study may provide a novel therapeutic approach for the treatment of RA.
中文摘要 ........................................................................................................I
Abstract .........................................................................................................III
誌謝 ................................................................................................................V
目錄 ................................................................................................................VI
圖表目錄 ........................................................................................................IX
附錄 ................................................................................................................XI
縮寫 ................................................................................................................XII
緒論(Introduction) .......................................................................................1
類風濕性關節炎 (rheumatoid arthritis, RA) ............................................1
RA致病機轉 .............................................................................................1
RA與基因治療 .........................................................................................3
Galectin-1 (Gal-1) ......................................................................................4
Galectin-3 (Gal-3) ......................................................................................6
慢病毒載體 (Lentiviral vector) ................................................................9
核醣核酸干擾 (RNA interference) ...........................................................10
膠原蛋白誘導關節炎 (Collagen-induced arthritis, CIA) ........................11
研究動機與實驗設計 ................................................................................12
材料與方法(Materials and Methods) .........................................................13
材料 ..............................................................................................................13
質體(plasmids) ...........................................................................................13
寡去氧核苷酸(oligodeoxynucleotides, ODN) ..........................................14
細胞株 ........................................................................................................16
實驗動物 ....................................................................................................16
方法 ..............................................................................................................16
細胞株與細胞培養 ....................................................................................16
構築表現Gal-1的慢病毒載體 .................................................................17
選殖大鼠的Gal-3 cDNA ...........................................................................17
Gal-3融合綠螢光質體建構與設計篩選Gal-3的RNA干擾素 ...............18
質體的轉染 ................................................................................................18
RNA 的分離與RT-PCR ...........................................................................19
西方墨點法(Western blot)  .......................................................................20
生產重組慢病毒載體 ................................................................................21
定量病毒的效價(titer) ...............................................................................22
第二型膠原蛋白誘發關節炎(type II collagen-induced arthritis; CIA) ....23
大鼠臨床上關節炎的病徵評估 ................................................................23
組織病理學分析(Histopathologic analysis) ..............................................24
X光攝影評估 ............................................................................................24
免疫組織化學染色分析(Immunohistochemical analysis)  ......................24
統計分析 ....................................................................................................25
實驗結果(Results) ........................................................................................26
大鼠Gal-3 cDNA的選殖 ..........................................................................26
篩選有效的Gal-3 shRNA .........................................................................26
生產重組慢病毒載體Lt.Gal-1與Gal-1基因表現 ...................................27
生產重組慢病毒載體Lt.shGal-3與抑制Gal-3蛋白表現 .......................28
探討Gal-1與Gal-3的表現與疾病的相關性 ...........................................29
重組慢病毒攜帶基因於關節內的表現 ...................................................29
CIA大鼠中Lt.Gal-1與Lt.shGal-3的預防性治療效果(prophylactic effects) ......................................................................................................30
Lt.Gal-1與Lt.shGal-3治療後的CIA大鼠之組織病理學分析 ...............30
Lt.Gal-1與Lt.shGal-3治療後的CIA大鼠之X光攝影分析 ...................31
淋巴節細胞在增加Gal-1表現與降低Gal-3表現後更容易受到抗原刺激死亡 ......................................................................................................31
經由給予Gal-1基因或Gal-3 shRNA降低大鼠關節炎之血管新生 ......32
藉由增加Gal-1基因表現或減少Gal-3 基因表現降低大鼠關節炎之T細胞浸潤 .................................................................................................32
討論(Discussion) ...........................................................................................34
參考文獻(References) ..................................................................................37
圖表(Figures) ................................................................................................47
附錄(Appendix) ............................................................................................63
自述 ...............................................................................................................67
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