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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 胡忠怡(Chung-Yi Hu) | |
| dc.contributor.author | Yu-Jyun Chen | en |
| dc.contributor.author | 陳煜均 | zh_TW |
| dc.date.accessioned | 2021-06-13T01:03:55Z | - |
| dc.date.available | 2007-08-08 | |
| dc.date.copyright | 2007-08-08 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-07-24 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29286 | - |
| dc.description.abstract | 介白素-15 (IL-15)為一種吸附於細胞膜之細胞激素，主要藉助與IL-15受器體α次元結合而表現於樹突狀細胞(dendritic cells)和單核球(monocytes)細胞表面，功能為促進NK細胞、T細胞和B細胞的增生和分化，並促使細胞產生抗細胞凋亡蛋白Bcl-2。IL-15受器體(IL-15 receptor，IL-15R)為由α、β、γ三個次元所組成的異構三聚體(heterotrimer)，其中IL-15受器體α次元(IL-15Rα)對於IL-15結合具有高親和力。
全身性紅斑性狼瘡(Systemic Lupus Erythematosus，SLE)是一種由對抗自體抗原的抗體或是淋巴球 (autoantibodies or autoreactive lymphocytes)所引起全身性慢性發炎的自體免疫性疾病。除了產生多種自體抗體以外，全身性紅斑性狼瘡(SLE)病人在細胞層次上也有多種異常，可能都與SLE病人體內IL-15增加有關。先前的研究指出，大約有40%的SLE病人血清中IL-15的量高於於正常健康人；且血清中IL-15量的增加與其淋巴球Bcl-2表現量增加呈正相關。但於L. Baranda et al. 研究發現，儘管全身性紅斑狼瘡的病人血清中IL-15有增加的現象，來自於全身性紅斑性狼瘡病人的血液中的周邊血液單核球細胞 (PBMCs) 與T淋巴球細胞在受PMA或PHA刺激後，對於IL15的反應卻較健康對照組細胞差，且IL-15受器體的表現並沒有減少的情形，推測SLE病患IL-15受器體功能可能與正常對照組有差異。IL-15受器體α次元為IL-15R複合體中，對IL-15專一性且高親和力的次元，且根據基因剔除的老鼠表現型顯示，IL-15Rα在IL-15的正常生理功能上扮演重要的角色。故若IL-15受器體α次元發生變異，極可能導致細胞對於IL-15反應異常，參與了全身性紅斑性狼瘡的致病機制。故本篇研究以IL-15受器體α次元基因(IL15RA)為研究目標，研究IL15RA在基因單點核苷酸的變異與SLE發生之關聯性。 本篇論文主要在探索IL15RA基因之變異與全身性紅斑性狼瘡之相關性，並對全身性紅班性狼瘡的病人與健康對照組進行SNP定型(Typing)，討論IL15RA 基因上單點核苷酸多型性與疾病發生、疾病活性與臨床症狀的關係。在本研究中篩選的13個位於預測之轉錄調節子(regulatory element)與轉錄子(exon)的SNP後，選定了3個在台灣族群中具多型性的SNP (-646G/C、-565C/T、+627A/C)，進行大量檢體的定型。進行統計分析後，發現IL15RA +627A對偶基因型與SLE的發生有顯著的正相關(odds ratio =1.42, 95% confidence interval: 1.01-2.01, p: 0.044)；IL15RA半套体 (-646C/-565C/+627C)則與SLE呈高度負相關。(odds ratio=0.59, 95% CI: 0.40-0.87，p-value: 0.007)。 | zh_TW |
| dc.description.abstract | Interleukin-15, a membrane-bound cytokine, is mainly expressed on the surfaces of dendritic cells and monocytes through binding to the high affinity IL-15 receptor α subunit. IL-15 can stimulate the generation and differentiation of NK cells, T cells and B cells, and induce the production of anti-apoptotic protein, Bcl-2. IL-15 receptor (IL15R) is composed of α, β and γ subunits and IL-15 receptor α subunit (IL-15Rα) is a unique subunit for IL-15 with an extremely high affinity (Ka~1011M-1).
Systemic lupus Erythematosus is a systemic autoimmune disease characterized by chronic systemic inflammation disease, which is mediated by autoreactive lymphocytes or autoantibodies. In addition to the production of various antibodies, patients with SLE suffer from many cellular abnormalities, and all the abnormalities could be attributed to the increasing of IL-15 in the sera of patients with SLE. In comparison with healthy control population, IL-15 was found to be elevated in 40% of SLE patients, and the amount of serum IL-15 is correlated with the amount of Bcl-2 in lymphocytes from patients. In spite of elevated serum IL-15 in SLE patients, PBMCs and lymphocytes from SLE patients showed poor responses to recombinant IL-15 and PHA than cells from healthy controls, without diminished expression of IL-15Rα, which suggested an altered function or expression of IL-15 receptor in SLE leukocytes. According to the same phenotypes between IL-15-/- mice and IL-15Rα-/- mice, IL-15Rα is viewed as a critical part in the normal physiological function of IL-15. Variances occur on IL-15Rα or IL15RA gene may result in poor cellular responses to IL-15. Therefore, IL15RA was chosen as candidate gene. Single nucleotide polymorphisms (SNPs) on IL15RA gene were analyzed and investigated if genetic variation of IL15RA gene would correlate to SLE development. Thirteen SNPs in the predicted regulatory elements and exonic regions, and three SNPs (-646G/C, -565C/T, +627A/C) were intensive studied in the SLE patients and the non-lupus control. The results indicated that IL15RA +627A allele was positively associated withSLE (odds ratio=1.42, 95% confidenence interval: 1.01-2.01, p: 0.044), and the haplotype (-646C/-565C/+627C) was significantly negatively correlated to SLE prevalence (odds ratio=0.59, 95% CI: 0.40-0.87, p: 0.007). | en |
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| dc.description.tableofcontents | 目錄......................................................I
中文摘要..................................................V 英文摘要................................................VII 第一章、 緒論 第一節、 全身性紅斑性狼瘡簡介.............................1 壹、 自體免疫疾病.....................................1 貳、 全身性紅斑性狼瘡.................................2 A. 全身性紅斑性狼瘡臨床症狀與診斷...................2 B. 全身性紅斑性狼瘡的流行病學.......................3 C. 自體抗體與全身性紅斑性狼瘡.......................5 第二節、 介白素-15與介白素-15受器體.......................6 壹、 介白素-15........................................6 A. 介白素-15........................................6 B. 介白素-15基因與蛋白質結構........................6 C. 介白素-15基因的表現..............................7 D. 介白素-15的轉錄與轉譯調控........................8 貳、 介白素-15受器體..................................8 參、 介白素-15受器體α次元.............................9 A. 介白素-15受器體α次元基因與蛋白質結構.............9 B. 介白素-15受器體α次元基因的表現..................10 C. 可溶性介白素-15受器體α次元......................11 肆、 介白素-15與介白素-2.............................12 伍、 介白素-15與SLE..................................12 第三節、 研究目的與實驗設計..............................14 第二章、 材料與方法 第一節、 材料............................................16 壹、 檢體收集........................................16 貳、 試劑清單........................................17 參、 試劑組..........................................18 肆、 聚合酶鏈鎖反應引子..............................18 A. IL15RA基因轉錄調節子區域(predicted regulatory element)聚合酶鏈鎖反應引子......................18 B. IL15RA基因第三轉錄子區域(13786~13496)聚合酶鏈鎖反 應引子..........................................19 C. IL15RA基因第四轉錄子區域(16552~16850)聚合酶鏈鎖反 應引子..........................................19 伍、 實驗儀器........................................19 陸、 軟體與網路工具..................................20 第二節、 試劑配方........................................21 第三節、 方法............................................23 壹、 Genomic DNA純化.................................23 貳、 介白素-15受器體α次元基因啟動子預測掃描..........24 參、 聚合酶鏈鎖反應..................................24 肆、 洋菜膠電泳分析..................................28 伍、 PCR產物純化.....................................29 陸、 PCR產物純化後核酸定序前處理.....................30 柒、 限制酶片段長度多型性分析........................30 第三章、 實驗結果 第一節、 全身性紅斑性狼瘡病人疾病活性之評估與臨床資料收集31 第二節、 介白素-15受器體α次元(IL15RA)基因單點核苷酸多型性 (SNP)之疾病相關候選SNPs篩選.....................32 壹、 IL15RA 基因轉錄調節子區域(regulatory element)預測 與疾病相關候選SNPs篩選..........................32 貳、 IL-15RA gene轉錄子(Exons)區域疾病相關候選SNPs篩選 ................................................33 第三節、 介白素-15受器體α次元疾病相關候選SNPs與SLE疾病關聯 分析 壹、 對偶基因型頻率(Allelic Frequency)分析...........35 A. 對偶基因型頻率與全身性紅斑性狼瘡發生之分析......35 B. -646G/C、-565C/T、+627A/C對偶基因型頻率與全身性紅 斑性狼瘡疾病活性與臨床症狀之分析................35 貳、 -646G/C、-565C/T、+627A/C基因型與全身性紅斑性狼瘡 發生、疾病活性與臨床症狀關聯分析................36 參、 -646G/C、-565C/T、+627A/C對偶基因型攜帶(Allelic Carriage)與全身性紅斑性狼瘡發生、疾病活性與臨床症 狀關聯分析......................................36 肆、 -646G/C、-565C/T、+627A/C半套體(Haplotypes)與全身 性紅斑性狼瘡發生、疾病活性與臨床症狀關聯分析...37 A. -646、-565、+627半套體基因型預測................37 B. -646G/C、-565C/T、+627A/C半套體基因型與疾病的發 生、疾病活性與臨床症狀分析......................37 第四章、 討論............................................39 第五章、 參考文獻........................................42 圖表.....................................................49 圖一、全身性紅斑性狼瘡病人年齡與疾病活性之分布.........50 圖二、IL15RA gene 5’端上游基因Promoter scan結果.......51 圖三、限制酶片段長度多型性實驗分析第四轉錄子單點核苷酸變 異627A/C.........................................52 表一、小規模先趨測試國人樣本已發表之各SNP點基因變異之分布 .................................................53 表二、IL15RA SNP位點基因型分析結果.....................54 表三、IL15RA SNP位點Allelic frequency與臨床症狀分析結果55 表四、IL15RA -646、-565、+627位點基因型與SLE發生與疾病活 性關聯分析.......................................57 表五、IL15RA -646、-565、+627位點基因型與臨床症狀分析結果 .................................................58 表六、IL15RA -646G/C、-565C/T、+627A/C位點對偶基因攜帶與 SLE發生及疾病活性關聯分析........................60 表七、IL15RA -646G/C、-565C/T、+627A/C位點對偶基因攜帶與 臨床症狀分析結果.................................61 表八、Program EH version 1.20預測-646G/C、-565C/T、 +627A/C之半套體(Haplotypes)......................63 表九、IL15RA半套體基因型(Haplotypes)與SLE發生及疾病活性關 聯之分析.........................................64 表十、IL15RA -646G/C、-565C/T、+627A/C半套體基因型與臨床 症狀分析結果.....................................65 附錄.....................................................67 附錄一、The American College of Rheumatology criteria for classification of SLE......................68 附錄二、The Systemic Lupus Erythematosus disease activity index (SLEDAI)........................69 附錄三、IL-15的基因與一級蛋白質結構....................70 附錄四、IL-15 receptor.................................71 附錄五、IL-15Rα基因與蛋白質結構........................72 附錄六、IL-15與IL-2在基因結構、蛋白質結構與訊息傳遞之比較 ...............................................73 附錄七、Nucleotide abbreviation to represent ambiguity.74 | |
| dc.language.iso | zh-TW | |
| dc.subject | 酸多型性 | zh_TW |
| dc.subject | 全身性紅斑性狼瘡 | zh_TW |
| dc.subject | 介白素-15 | zh_TW |
| dc.subject | 介白素-15受器體α次元 | zh_TW |
| dc.subject | 單點核苷 | zh_TW |
| dc.subject | interleukin-15 receptor alpha (IL-15Rα) | en |
| dc.subject | Single nucleotide polymorphism (SNP) | en |
| dc.subject | Systemic lupus erythematosus (SLE) | en |
| dc.subject | interleukin-15 | en |
| dc.title | 介白素-15受器體-α次元基因變異於全身性紅斑狼瘡之研究 | zh_TW |
| dc.title | Investigating Association of IL15RA Genetic Variation in Systemic Lupus Erythematosus | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 許秉寧,孫光蕙,楊雅倩 | |
| dc.subject.keyword | 全身性紅斑性狼瘡,介白素-15,介白素-15受器體α次元,單點核苷,酸多型性, | zh_TW |
| dc.subject.keyword | Systemic lupus erythematosus (SLE),interleukin-15,interleukin-15 receptor alpha (IL-15Rα),Single nucleotide polymorphism (SNP), | en |
| dc.relation.page | 74 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-07-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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