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研究生:梁啟榮
研究生(外文):Chi Jung Liang
論文名稱:孤兒G蛋白偶聯受體,GPCR109B及GPCR43,在藥物誘導K562人類血癌細胞株分化過程扮演不同角色
論文名稱(外文):Orphan G Protein-Coupled Receptors, GPCR109B and GPCR43, Play Different Roles In Chemical Induced K562 Human Leukemia Cell Differentiation
指導教授:李泰林李泰林引用關係蔡明勳蔡明勳引用關係
指導教授(外文):Tai Lin LeeMing Shiun Tsai
學位類別:碩士
校院名稱:大葉大學
系所名稱:生物產業科技學系
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:90
中文關鍵詞:G蛋白配體標靶治療巨噬細胞巨核細胞
外文關鍵詞:G proteinLigandTarget therapymacrophagemegakaryocyte
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  • 被引用被引用:1
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G蛋白偶聯受體(G protein-coupled receptor, GPCR)為人類廣泛存在之蛋白質的一個族群,其扮演之角色主要為細胞訊息傳遞過程中之媒介者(Mediators)。當細胞表面GPCR受到專一或非專一性配體(Ligand)結合時,可刺激G蛋白並將訊息傳遞至下游,造成一連串的瀑布(cascade)效應。很多疾病的產生,即是因為GPCR功能的喪失或是藥物濫用後影響其訊息途徑所造成。困於目前對於大部分的GPCR在生理上之功能性尚未完全了解,實際用於治療的應用不多。若可結合特殊配體與受體之間之專一性作用,未來應用在開發新藥物治療或標靶治療(Taget Therapy)上的願景是可期待的。
G蛋白為細胞訊息傳遞中重要媒介角色,其可接受來自GPCR的一級訊號再將其轉變成二級訊號進一步傳遞下去。文獻預測GPCR109B及GPCR43此兩受體分別會影響下游G蛋白次單元Gαi及Gα11之訊息傳遞。本論文研究目的主要釐清此兩受體是否會影響血球細胞功能性基因表現的變化,而希望藉由了解此傳遞之路徑,試圖找出治療血癌或貧血等疾病的契機。
當過量表現GPCR109B後,添加其配體N-amino nicotinate作用,會明顯增加血小板生長因子(Platelet-derived growth factor, PDGF)表現;而GPCR43與其配體丙酸鹽(propionate)結合則會抑制PDGF的表現。血球巨核細胞分化因子(Tescalcin, TESC)在此兩受體中皆沒有顯著的差異。在GPCR109B過量表現時γ球蛋白有明顯的減少,但GPCR43則沒有顯著影響。而當延長細胞誘導時間後,在GPCR109B部份,Vimentin的表現量則有明顯的升高,GPCR43則是TESC有明顯的增加。綜合此結果結合細胞型態的判斷,暗示此兩受體訊息傳遞路徑可能是不同的,GPCR43可能會影響細胞走向巨核細胞分化途徑,而GPCR109B則可能與巨噬細胞分化有關聯。
G protein-coupled receptors, GPCRs, widely exist as a protein family in the human genome, and are the main signal transduction media. When a GPCR is binding with its non- or specifitic ligand, it can stimulate, also, scale up the signal. After the signal transducted to down stream, the cascaded bioeffects are resulted. Lot of diseases are resulted from the malfunctions or lost of functions of GPCRs. Currently, the understands of the GPCRs are still poor, these result in the un-wide application. If we can connect receptors with their specific ligands, we may open the gate in the application of new medicine or target therapy.
G proteins are importment media of the celleular signal cascades, they accept primary messages from the GPCR, and transfer to secondary messages produced, subsequently deliver to down stream target. In this thesis, the possible down-stream targets of two GPCRs are studied. From these results, we may provide information to find the candidate of leukemia or anemia disease therapies.
Our preliminary results show when overexpression of GPCR109B and accompanied with 6-amino-nicotinate admiseration, the ligand of GPCR109B. PDGF, expression levels have strikingly increased. However overexpression of GPCR43 represses the expression of PDGF. The expession of TESC has no difference at two days after GPCR43 or GPCR1109B overexpression. However, when extend the cell incubation period to 6 days, Vimentin administration shows significant increase the expression level of GPCR109B, and TESC increase the expression level of GPCR43. In combination with the results of Real-time PCR and cell mophotype, we suggest that the GPCR109B and GPCR43 pathways are different, expression of GPCR43 may lead K562 leukemia to differentiate into megakaryocytes, and expression of GPCR109B may lead to the macrophages.
封面內頁
簽名頁
授權書iii
中文摘要iv
英文摘要vi
誌謝vii
目錄viii
圖目錄xii
1. 緒言1
2. 文獻回顧2
2.1 G蛋白偶聯受體2
2.1.1 G蛋白偶聯受體的功能2
2.1.2 GPCR的分子結構及其功能性3
2.1.3 GPCR的分類及及性3
2.1.3.1 Rhodopsin3
2.1.3.2 Adhesion4
2.1.3.3 Glutamate5
2.1.3.4 Frizzled/Taste25
2.1.3.5 Secretin6
2.2 GPCR43之相關研究7
2.3 GPCR109B之相關研究8
2.4 G蛋白(G-protein)9
2.5血小板延生生長因子在細胞中的角色10
2.6 Tescalcin (TESC) 在細胞中的角色11
2.7 Vimentin (Vim) 在細胞中的角色12
2.8血液相關疾病13
2.8.1血癌13
2.8.1.1細胞增生與癌細胞之形成14
2.8.2貧血15
2.8.3人類血癌細胞株K562細胞17
2.9研究動機及目的18
2.9.1血癌治療(Leukemia therapy18
2.9.2 GPCR109B及GPCR43受體與訊息傳遞的角色19
3. 研究方法21
3.1材料21
3.1.1菌種及細胞株21
3.1.2培養基21
3.1.3染劑21
3.1.4配體(Ligand)22
3.1.5載體22
3.2方法22
3.2.1培養基的配製22
3.2.1.1 RPMI1640培養基22
3.2.1.2透析血清製備23
3.2.2配體的合成23
3.2.3細胞計數及其繼代培養23
3.2.4細胞分化之判定24
3.2.5 Wright-Giemsa Stain Method24
3.2.6 6-ANA及propionic acid毒性測試24
3.2.7 RNA萃取與cDNA製備25
3.2.7.1 RNA萃取 (RNA extration)25
3.2.7.2反轉錄聚合酶鏈鎖反應25
3.2.7.3即時定量聚合酶鏈鎖反應(real-time PCR)26
3.2.7.4洋菜膠膠體電泳27
3.2.8限制酵素剪切作用(Restriction enzyme digestion)27
3.2.9接合作用(Ligation)27
3.2.9.1 PCR產物之選殖接合作用27
3.2.9.2表現載體接合作用28
3.2.10勝任細胞(competent cell)其質體選殖之轉型作用28
3.2.11質體DNA萃取(Mini-extration)28
3.2.12質體DNA的轉染(transfection)29
3.2.12.1微溶體(Liposome)轉染29
3.2.12.2電穿孔(Electroporator)轉染29
3.2.13西方墨點法(Western blot)29
3.2.14穩定表現株的建立30
4. 結果與討論31
4.1 GPCR109B及GPCR43的表現31
4.2 GPCR109B細胞分化之角色31
4.2.1 GPCR109B之構築31
4.2.2 GPCR109B配體6-ANA之細胞毒性(cytotoxicity)31
4.2.3 GPCR109B誘導K562分化為單核/巨噬細胞32
4.2.3.1細胞型態32
4.2.3.2單核/巨噬細胞之指標性基因32
4.3 GPCR43細胞分化之角色33
4.3.1 GPCR43之構築33
4.3.2 GPCR43配體6-ANA之細胞毒性(cytotoxicity)33
4.3.3 GPCR43誘導K562分化為單核/巨噬細胞33
4.3.3.1細胞型態33
4.3.3.2單核/巨噬細胞之指標性基因34
4.4討論34
5. 結論38
參考文獻54
附錄64
圖目錄
圖1誘導劑誘導K562細胞後對GPCR43及GPCR109B表現量的影響39
圖2GPCR109B的選殖及表現載體的構築40
圖3NCBI之GPCR109B序列(BC047891)與選殖GPCR109B序列比對41
圖4GPCR109B配體6-ANA對K562細胞生長的影響42
圖5質體轉染後GPCR109B在K562細胞中的表現43
圖6GPCR109B在K562細胞短暫性轉染後PDGF、TESC及γ-globin之表現44
圖7GPCR109B在K562細胞短暫性轉染後TESC及Vim之表現45
圖8GPCR43的選殖及表現載體之構築46
圖9NCBI之GPCR43序列(NM_005306)與選殖GPCR43序列比對47
圖10GPCR43配體propionic acid對K562細胞生長的影響48
圖11質體轉染後GPCR43在K562細胞中的表現49
圖12GPCR43在K562細胞短暫性轉染後PDGF、TESC及γ-globin之表現 50
圖13GPCR43在K562細胞短暫性轉染後TESC及Vim之表現51
圖14Control、GPCR109B及GPCR43短暫性轉染後利用Giemsa染色細胞52

圖15GPCR109B及GPCR43穩定表現株的細胞型態53
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