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系統識別號 U0026-1307201121451900
論文名稱(中文) 探討Klf10基因缺失鼠與第二型糖尿病之關聯性
論文名稱(英文) Study the correlation between Klf10 deficiency mice and type-2 diabetes mellitus
校院名稱 成功大學
系所名稱(中) 生命科學系碩博士班
系所名稱(英) Department of Life Sciences
學年度 99
學期 2
出版年 100
研究生(中文) 林峻宇
研究生(英文) Chun-Yu Lin
電子信箱 l56981026@mail.ncku.edu.tw
學號 l56981026
學位類別 碩士
語文別 中文
論文頁數 135頁
口試委員 召集委員-施能耀
口試委員-宋皇模
指導教授-張虹書
中文關鍵字 基因缺失鼠  第二型糖尿病 
英文關鍵字 KLF10  knockout mice  T2DM 
學科別分類
中文摘要   第二型糖尿病是現今社會人口中,發生率與盛行率極高的慢性代謝疾病,其主要肇因為不正常的飲食習慣與生活型態所導致之肥胖。此生理現象易引發體內胰島素的分泌與作用失常,使個體產生高血糖、高血脂的症狀,最終導致器官損傷而衰竭。至2030年,國際糖尿病聯盟預估全球罹患糖尿病的人數將會達到四億三千八百萬人左右,因此對於第二型糖尿病的治療,除臨床上的投藥與維持良好生活作息及飲食的建議外,相關基礎研究日益漸多,期望能找到治癒第二型糖尿病的方法。然使個體產生糖尿病的原因除上述外,許多臨床研究也已初步指出,糖尿病患者體內某些調控醣類和脂質代謝的相關基因,其表現和正常個體有所差異,而本論文所研究的目標基因─Klf10,即為這些表現異常的基因之一。KLF10除調控細胞增生、分化、凋亡等發育過程外,也被許多文獻明確指出參與在醣類和脂質的代謝過程中。近年研究更發現,KLF10對於胰島素的合成與分泌,以及第二型糖尿病的病程發生有一定之關聯性。然而,KLF10影響這些代謝過程的詳細機制為何,目前仍未明朗。本論文旨在探討KLF10在代謝與糖尿病中扮演的角色,試驗將以高油脂飼料,誘導全身性Klf10基因剔除鼠產生第二型糖尿病病徵,業經測定其基本生理、生化數值發現,Klf10基因剔除公鼠於體重、空腹血糖、血中胰島素等數值與正常公鼠具差異性,然Klf10基因剔除正常之母鼠差異性則較小;另經口服葡萄糖耐受性測試,Klf10基因剔除鼠較正常小鼠明顯呈現葡萄糖不耐之現象;取其組織作切片觀察細胞形態,發現Klf10基因剔除小鼠胰臟β-細胞排列較正常小鼠鬆散,細胞體積也較小;另業經微陣列分析兩者肝臟中基因表現模式,可發現許多參與醣類、脂質代謝和胰島素作用的基因具表現差異性。綜合上述結果,證實KLF10確實參與醣類和脂質代謝過程,並在高油脂飼料誘導下,具調節與維持體內醣類恆定與胰島素阻抗之功能,可推論其在第二型糖尿病病程發展過程中,扮演抑制的角色。
英文摘要 Type-2 diabetes mellitus (T2DM) is a modern metabolic syndrome associated with high incidence in nowadays, which is developed because of obesity with abundant diet-intake habits and abnormal life-style. The individual with obesity will present some negative physiological traits such as hyperglycemia and hyperlipidemia caused by insulin secretion decrease and action failure, finally, to make organs dysfunctions. International Diabetes Federation predicted that the population suffering T2DM will increase to 438 million in worldwide when 2030. To improve treatment effects of T2DM, not only giving medicine clinically but many basic researches are on the way. Many fundamental studies had indicated that there were some genes involved in carbohydrates and lipids metabolism express differentially in T2DM patients compared with normal guys. Klf10, the gene we study is one of them, however, the detail mechanisms of KLF10 act in metabolism still unclear so far. According to studies in the past, KLF10 mainly execute its functions on cell growth, tissue development, cell differentiation and apoptosis. Moreover, recent studies indicated roughly that KLF10 also make a rule in metabolism of carbohydrates and of lipids, secretion of insulin, and T2DM. The goal of the thesis is to figure out how about KLF10 act in metabolism and T2DM. To get this, we have created a constitutive Klf10 knockout mice model for relative study. To induce mice presenting some phenotypes of T2DM, we subjected them to high-fat diet fedding and then measure their basic physiological and biochemical values. As results, the basic physiological and biochemical values such as body weight, fasting blood glucose, fasting blood triglycerides, and fasting blood insulin had been shown different alteration between male normal and male Klf10 knockout mice, although there was less significant difference in female mice. By oral glucose tolerance test, Klf10 knockout mice fed with high-fat diet presented poor glucose tolerance than normal mice during test periods (2 hours). On the other hand, the pancreatic cell arrangement of Klf10 knockout mice was looser than normal mice, and cell mass reduced in their tissue specimen. Furthermore, genes expressed in liver involving in carbohydrates and lipid metabolism also shown significant difference between male normal and male Klf10 knockout mice performed by microarray analysis. In conclusions, KLF10 is indeed involved in carbohydrates and lipids metabolism, as well as insulin resistance, and could regulate glucose homeostasis by maintain glucose tolerance of individual subjected to high-fat diet. These results indicated that KLF10 is a potential suppressor in development of T2DM.
論文目次 中文摘要 I
Abstract II
致謝 IV
目錄 VI
縮寫檢索表 X
第一章 緒論 1
一、 前言 1
二、 文獻探討 2
壹、 Krüppel-like factor轉錄因子 2
貳、 KLF10 和KLF11蛋白轉錄因子 4
參、 第二型糖尿病(Type 2 Diabetes Mellitus, T2DM) 8
三、 實驗動機與目的 16
第二章 材料與方法 17
一、 Klf10基因剔除鼠動物模式之建立 17
1. 篩選小鼠Klf10序列及建構Klf10基因剔除載體 17
2. 胚胎幹細胞之培養、轉染及基因剔除胚胎幹細胞之選殖 17
3. 胚胎幹細胞DNA的製備及南方墨點法 18
4. Cre重組酶轉染胚胎幹細胞 18
5. 囊胚期細胞注射,嵌合鼠之育種及基因剔除鼠基因型鑑定 18
6. 全身性Klf10基因剔除鼠(constitutive Klf10 knockout mice)育種 19
7. 條件性Klf10基因剔除鼠(conditional Klf10 knockout mice)育種 19
二、 第二型糖尿病鼠動物模式之建立 19
三、 動物飼育 20
1. 純品系之小鼠 20
2. 基因剔除小鼠 20
四、 Klf10基因剔除鼠之基因型鑑定(Genotyping) 21
1. 小鼠記號標定 21
2. 組織基因體DNA(genomic DNA)萃取 21
3. 基因型鑑定聚合酶鏈鎖反應(Genotyping Polymerase Chain Reaction) 22
4. DNA洋菜膠電泳分析 23
五、 眼窩採血 24
六、 血漿樣本製備 25
七、 血液生化數值測定 25
八、 血液胰島素濃度測定 25
九、 口服葡萄糖耐受性測試 26
十、 組織切片與組織免疫染色 27
1. 灌流(perfusion) 27
2. 摘取組織器官 28
3. 組織脫水、滲蠟與包埋 28
4. 石蠟切片 30
5. Hematoxylin and Eosin (H&E) 染色法 30
十一、 微陣列(Microarray)分析 32
第三章 實驗結果 33
一、 建構全身性Klf10基因剔除鼠及其基因型鑑定 33
二、 統計Klf10+/-基因型之F2子代小鼠相互交配所得之F3子代小鼠數目 33
三、 胰臟特異性Klf10基因剔除鼠的基因型鑑定 34
四、 以高油脂飼料誘導小鼠產生第二型糖尿病病徵並測定其血液生化數值 35
1. Klf10基因剔除公鼠體重較正常公鼠輕 35
2. Klf10基因剔除鼠和正常小鼠的血糖濃度具差異性變化 35
3. 正常與Klf10基因剔除鼠血中三酸甘油脂濃度無差異性 36
4. 比較正常與Klf10基因剔除鼠的血中胰島素濃度 36
五、 餵食高油脂飼料之Klf10基因剔除鼠具較高的胰島素阻抗性 37
六、 探討正常與Klf10基因剔除鼠對葡萄糖的耐受度差異 38
七、 比較高油脂飼料誘導之正常與Klf10基因剔除鼠細胞形態 39
八、 高油脂飼料誘導之正常與Klf10基因剔除公鼠基因表現 39
第四章 討論 41
一、 組織特異性Klf10基因剔除鼠之建立 41
二、 全身性Klf10基因剔除鼠F3子代數目不符合孟德爾定律 41
三、 正常與Klf10基因剔除鼠之間體重之差異性 42
四、 餵食標準飼料的Klf10基因剔除鼠空腹血糖值較正常小鼠低 43
五、 Klf10基因剔除公鼠較母鼠具有數值測定上的差異性 43
六、 Klf10與葡萄糖和胰島素之間的相關性 44
七、 探討餵食高油脂飼料之正常與Klf10基因剔除公鼠細胞形態差異 45
八、 利用微陣列分析參與在糖類與之脂質代謝的基因表現之差異 45
參考文獻 47
實驗圖表 54
表一、本論文所使用之引子序列 54
表二、全身性Klf10基因剔除鼠F3子代基因型暨隻數統計表 55
表三、餵食高油脂飼料之Klf10基因剔除鼠肝臟中基因具差異性表現提升列表 56
表四、餵食高油脂飼料之Klf10基因剔除鼠肝臟中基因具差異性表現下降列表 81
圖一、以基因體聚合酶鏈鎖反應分析全身性Klf10基因剔除鼠基因型 101
圖二、全身性Klf10基因剔除鼠子代的基因型鑑定 102
圖三、胰臟特異性Klf10基因剔除鼠基因型鑑定策略 103
圖四、Klf10F/F基因型小鼠與帶有Pdx1-Cre序列之基因重組小鼠交配所得子代之基因型鑑定 104
圖五、比較餵食正常飼料之正常與Klf10基因剔除鼠體重改變情形 105
圖六、比較餵食高油脂飼料之正常與Klf10基因剔除鼠體重改變情形 106
圖七、比較餵食正常飼料之正常與Klf10基因剔除鼠血糖改變情形 107
圖八、比較餵食高油脂飼料之正常與Klf10基因剔除鼠血糖改變情形 108
圖九、比較餵食正常飼料之正常與Klf10基因剔除鼠血中三酸甘油脂改變情形 109
圖十、比較餵食高油脂飼料之正常與Klf10基因剔除鼠血中三酸甘油脂改變情形 110
圖十一、比較餵食正常飼料之正常與Klf10基因剔除鼠血液中胰島素改變情形 111
圖十二、比較餵食高油脂飼料之正常與Klf10基因剔除鼠血液中胰島素改變情形 112
圖十三、比較餵食正常飼料之正常與Klf10基因剔除鼠HOMA-IR數值 113
圖十四、比較餵食高油脂飼料之正常與Klf10基因剔除鼠HOMA-IR數值 114
圖十五、餵食正常飼料的正常與Klf10基因剔除公鼠,接受口服葡萄糖耐受性測試(OGTT)後兩小時期間血糖改變情形 115
圖十六、餵食正常飼料的正常與Klf10基因剔除母鼠,接受口服葡萄糖耐受性測試(OGTT)後兩小時期間血糖改變情形 117
圖十七、餵食高油脂飼料的正常與Klf10基因剔除公鼠,接受口服葡萄糖耐受性測試(OGTT)後兩小時期間血糖改變情形 119
圖十八、餵食高油脂飼料的正常與Klf10基因剔除母鼠,接受口服葡萄糖耐受性測試(OGTT)後兩小時期間血糖改變情形 121
圖十九、餵食高油脂飼料的正常與Klf10基因剔除公鼠組織切片比較 123
圖二十、餵食高油脂飼料的正常與Klf10基因剔除公鼠組織切片比較 124
圖二十一、餵食高油脂飼料之正常與Klf10基因剔除公鼠基因表現差異與功能分群 125
實驗附錄 126
附錄一 126
附錄二 127
附錄三 128
附錄四 129
附錄五 130
附錄六 131
附錄七 132
附錄八 133
附錄九 134
作者自述 135

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