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研究生:張延瑞
研究生(外文):Yen-Jui Chang
論文名稱:飢餓激素抗體之製作,檢定,及應用
論文名稱(外文):The Production, Characterization, and Application of Anti-Ghrelin Antibodies
指導教授:王錫崗王錫崗引用關係
指導教授(外文):Paulus S. Wang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:103
語文別:中文
論文頁數:151
中文關鍵詞:飢餓激素多株抗體發射免疫檢定甲狀腺功能低下壬基酚
外文關鍵詞:ghrelinpolyclonal antibodiesradioimmunoassayhypothyroidismnonylphenol
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飢餓激素是一種二十八個胺基酸所組成的胜肽,由胃部胃酸腺內的內分泌細胞所製造分泌;在第三個胺基酸,即絲胺酸上添加一個辛醯酸的側鏈後,可成為活性飢餓激素,是促生長激素分泌受體的內生性配體,可刺激腦下腺前葉分泌生長激素。飢餓激素另一重要的功能,為刺激下視丘引發飢餓的感覺而啟動進食,是近十年來被大量研究探討的一個胃腸胜肽。本實驗室利用牛血清白蛋白和鑰孔貝血藍蛋白為人類或大鼠飢餓激素之載體,於紐西蘭白兔製作出抗人類飢餓激素抗血清 YJC R7-36,MCC R8-41,YJC R-1-19,以及抗大鼠飢餓激素抗血清YJC R13-31,建立放射線免疫檢定之檢驗系統,應用於實驗中。在 Sprague-Dawley 大鼠的動物實驗中,首先印證禁食會造成飢餓激素血清濃度的提升;在年幼大鼠的壬基酚曝露實驗中,發現壬基酚會抑制因強迫灌食所造成的血清飢餓激素和血漿皮質酮濃度的上升;進而發現,對甲狀腺低下大鼠的實驗中,首次發現甲狀腺低下干擾了飢餓激素 / GHS-R軸線,和生長激素 / IGF-1 軸線的功能。應用於人類的實驗中,也先印證禁食會造成血清飢餓激素濃度上升和血清葡萄糖濃度下降,再以飢餓激素做為飢餓指標,發現為糖尿病患者發展出的流質配方食物,食用後三小時內其飢餓感覺與一般混合性食物的飢餓感覺並沒有差異。
Ghrelin is a growth-hormone-releasing acylated peptide isolated from the stomach as an endogenous stimulator for growth hormone secretagogue receptors (GHS-R). An n-octanoyl acid is bound at the serine 3 position to form active ghrelin, and only active ghrelin is able to stimulate the secretion of growth hormone. This highly conserved peptide is primarily produced by cells in the oxyntic glands of the stomach, and is released into the bloodstream. It has recently been speculated that ghrelin regulates food intake and energy balance. In the past 10 years, ghrelin is intensively investigated worldwide. By conjugating to bovine serum albumin or Keyhole limpet hemocyanin, our lab have produced anti-human ghrelin antiserum YJC R7-36, MCC R8-51, YJC R1-19, and anti-rat ghrelin antiserum YJC R13-31 in New Zealand Rabbits. These antiserum were used to establish radioimmunoassay system to measure ghrelin in various types of sample. In studies on Sprague-Dawley rats, the enhancement of ghrelin secretion in fasting condition was confirmed firstly. The experiment on young rats indicated that nonylphenol would inhibit the elevation of serum ghrelin and plasma corticosterone caused by forced-gavage. In studies on hypothyroid rats, plasma ghrelin levels increased but serum IGF-1 levels decreased in hypothyroid rats. These results suggested that the hypothyroid condition is able to interfere ghrelin/GHS-R axis as well as the growth hormone/IGF-1 axis. In the human studies, the elevation of serum ghrelin levels by fasting was found and confirm the usefulness of self-produced antiserum. The following experiment revealed that ordinary sandwich and liquid formula Glucerna SR have similar hunger sense by using ghrelin as an objective hunger index.
目錄
中文摘要 i
Abstract ii
目錄 iii
中英文名詞對照表及英文縮寫 vii
圖錄 viii
表錄 x
第壹章、文獻回顧 1
一、胜肽抗體之製作方法 2
(一) 實驗用抗體之特性 2
(二) 改善抗體品質的方法 3
(三) 胜肽和載體之接合 4
(四) 佐劑的使用 8
二、飢餓激素及其生理功能 9
(一) 飢餓激素之特性與相關疾病 9
(二)飢餓激素/促生長激素分泌受體軸線 12
(三)飢餓激素分泌的調控 12
(四) 壬基酚對飢餓激素分泌的效應 14
(五) 飢餓激素血漿濃度應用為客觀性飢餓指標 15
三、目的與假說 17
(一) 目的 17
(二) 假說 17
第貳章、材料與方法 18
一、實驗動物 19
二、人類受試者 19
三、飢餓激素抗體的製作 20
(一) 飢餓激素與載體接合及乳化 20
(二) 採血、接種、和放射線力價檢定 22
(三) 飢餓激素抗體之定性 23
四、品管樣本之組織蛋白質抽取 25
(一) 腦組織蛋白質抽取 25
(二) 胃組織胜肽酸性抽取法 26
五、血清或血漿中各種激素之檢測 26
(一) 人類或大鼠飢餓激素 RIA 26
(二) 大鼠皮質酮 RIA 27
(三) 血中葡萄糖和其他激素測定 27
六、西方墨點分析法 27
(一) 組織蛋白質的萃取及定量 27
(二) 十二烷基硫酸鈉聚丙烯酰胺凝膠電泳及西方點漬法 28
七、動物實驗 30
(一) 禁食對血清中飢餓激素之效應 30
(二) 年幼大鼠於強迫灌食壓力下,NP 對飢餓激素分泌之效應 30
(三) 大鼠甲狀腺切除對飢餓激素及其下游受體及激素之效應 31
八、人體試驗 32
(一) 禁食對人類血清飢餓激素及葡萄糖之效應 32
(二) 流質配方食物與一般食物對血中葡萄糖、胰島素、和飢餓激素之效應 32
九、飢餓激素之碘化 33
十、統計分析 34
第參章、抗體製作之結果與討論 35
一、以天竺鼠、安哥拉兔、及紐西蘭白兔製作抗體 37
二、抗血清 YJC R736 之定性 47
三、抗血清 MCC R841 之定性 49
四、抗血清 YJC R1331 之定性 61
五、抗血清 YJC R119 之定性 63
第肆章、抗飢餓激素抗體之應用與討論 65
一、禁食對大鼠血清飢餓激素濃度之效應 66
(一) 結果 66
(二) 討論 66
二、年幼大鼠於強迫灌食壓力下,NP 對飢餓激素分泌之效應 68
(一) 結果 68
(二) 討論 68
三、大鼠甲狀腺切除對飢餓激素及其下游受體及激素之效應 71
(一) 結果 71
(二) 討論 74
四、禁食對人類血清飢餓激素及葡萄糖之效應 87
(一) 結果 87
(二) 討論 87
五、流質配方食物與一般食物對人類血中葡萄糖、胰島素、和飢餓激素之效應 89
(一) 結果 89
(二) 討論 90
六、飢餓激素之碘化 99
(一) 結果 99
(二) 討論 99
結論 101
參考文獻 103
附錄 113
個人履歷 114
已接受發表之論文 120

Radioimmunoassay for Ghrelin: Evaluation of
Method and the Effect of Fasting in Rats 121

A Radioimmunoassay for Rat Ghrelin: Evaluation of Method and Effects of Nonylphenol on Ghrelin Secretion in ForceFed Young Rats 126

Effects of Subacute Hypothyroidism on
Metabolism and GrowthRelated Molecules 134  

圖錄
圖一、鑰孔貝之外觀及其血藍蛋白之結構 7
圖二、胃酸腺內飢餓激素細胞之免疫電子顯微鏡照片 10
圖三、雌二醇與壬基酚之化學結構 14
圖四、飢餓激素與飢餓分數的關係 16
圖五、以真空馬達大量採取兔耳血 22
圖六、生產抗體動物之體重、接種、及採血記錄 39
圖七、(A) 七號兔, (B) 八號兔之抗血清力價測試記錄 41
圖八、(A) 十三號兔, (B) 一號兔之抗血清力價測試記錄 42
圖九、強度檢測試驗 (A) 七號兔,(B) 八號兔 43
圖十、強度檢測試驗 (A) 十三號兔,(B) 一號兔 45
圖十一、專一性測試 (A) 七號兔,(B) 八號兔 51
圖十二、專一性測試 (A) 十三號兔,(B) 一號兔 53
圖十三、標準曲線及QC樣本平行關係測試 (A) 七號兔,(B) 八號兔 55
圖十四、標準曲線及QC樣本平行關係測試 (A) 十三號兔,(B) 一號兔 58
圖十五、非禁食及禁食大鼠血漿的飢餓激素濃度 67
圖十六、灌食NP 對年幼大鼠血漿飢餓激素及皮質酮之效應 69
圖十七、四組大鼠於代謝籠中二週內之體重變化 76
圖十八、代謝籠中大鼠代謝數據之記錄 77
圖十九、甲狀腺功能低下對大鼠 (A) TSH,(B) 活性飢餓激素,(C) 全飢餓激素之效應 79
圖二十、甲狀腺功能低下對大鼠腦下腺前葉 GHSR1 於之蛋白質表現之效應 81
圖二十一、甲狀腺功能低下對大鼠 (A) 生長激素,(B) IGF1 之效應 83
圖二十二、大鼠TSH,活性飢餓激素,全飢餓激素,生長激素,及IGF1之相關性 84
圖二十三、大鼠每日單位體重進食量與活性飢餓激素,TSH,和 IGF1 之相關性 86
圖二十四、禁食對人類血清 (A) 飢餓激素,及 (B) 葡萄糖之效應 88
圖二十五、混合性食物試驗之結果 96
圖二十六、三明治和怡保康二組中,血漿葡萄糖,胰島素,和飢餓激素的相關性 98
圖二十七、以碘125碘化 (A) 人類或 (B) 大鼠飢餓激素之結果 100

表錄
表一、常使用的載體接合方法 5
表二、常使用的蛋白質載體 5
表三、抗體生產摘要 36
表四、人類受試者特徵 92
表五、比較三明治組及怡保康組血漿葡萄糖,胰島素,及飢餓激素對混合食物試驗之反應 93
表六、比較不同時段三明治組和怡保康組血漿中葡萄糖,胰島素,和飢餓激素對混合食物試驗之反應 94
表七、以皮爾森及部份相關性檢定,比較血漿葡萄糖,胰島素,及飢餓激素濃度在混合食物試驗中不同時段的相關性 95

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