過敏是一種現代人常見的疾病，難以預防以及治療，因為環境中過敏原的增加而造成現今過敏人口持續上升中，為了預防過敏的發生，可使用過敏原檢測及相關檢敏療法，但是目前醫療上可檢驗的過敏原種類太少。因此我們的目標是透過大腸桿菌系統大量表現並純化過敏原蛋白，以了解免疫反應引發的過敏分子機制，並應用在生物醫學檢測上。我們總共挑選18個過敏原蛋白作為研究目標，依序可分為五類，包括食物類 (Ara h 1、Ara h 2、Gly m 5和Pen a 1)，花粉類 (Phl p 1、Phl p 5、Amb a 1、Art v 1、Par j 2、Cry j 1、Cry j 2、Cup s 1、Jun a 2和Pla a 1)，橡膠類 (Hev b 5和Hev b 6)，毒液類 (Ves v 1) 以及真菌類 (Asp f 1)。將所有的過敏原基因我們轉殖到pET22b或是pET28a的質體上，利用大腸桿菌系統進行蛋白質表現，再透過管柱層析法萃取蛋白質，並將過敏原蛋白合成抗體，以供日後作為生物醫學檢測上的應用。此外，我們希望透過結構生物學解析過敏原蛋白之晶體結構，更深入探討過敏原所造成的免疫反應之分子機制。

Allergy is a common disease for modern people, and is difficult to prevent and treat. Due to the increase of allergens in the modern environment, people suffering allergy become more and more. Hypersensitivity to allergy can be prevented by combining allergen specific tests and immunotherapy, but the types of allergens that have been tested are very few. Therefore, we aim to purify allergenic proteins in large scale through the E.coli expression system in order to understand the mechanism of allergen induced by immune responses and for applyication in biomedical detection. We selected 18 allergenic proteins, which are divided into five types: the food type (Ara h 1, Ara h 2, Gly m 5 and Pen a 1), the pollen type (Phl p 1, Phl p 5, Amb a 1, Art v 1, Par j 2, Cry j 1, Cry j 2, Cup s 1, Jun a 2 and Pla a 1), the rubber type (Hev b 5 and Hev b 6), the venom type (Ves v 1) and the microorganism type (Asp f 1). The allergenic genes were cloned into pET22b or pET28a plasmids and then expressed through the E. coli expression system. These proteins were further purified in a homogenous state by column chromatography and used on antibody synthesizion for application in biomedical detection. In addition, we will try to determine the crystal structures of these allergenic proteins to understand the allergen induced immune responses.

誌謝 i
中文摘要 ii
Abstract iii
目錄 iv
表目錄 vi
圖目錄 vii
縮寫及符號 ix
第一章 緒論 1
1.1 過敏反應 1
1.1.1 過敏反應之引發機制與病理症狀 1
1.1.2 過敏原蛋白之分類與來源 2
1.2 重組蛋白質表現之策略 5
1.2.1 菌種介紹 5
1.2.2 載體介紹 7
1.3 研究目的 7
第二章 材料與方法 8
2.1 質體構築 8
2.2 實驗菌種培養與保存 8
2.3 勝任細胞的製備 8
2.4 大腸桿菌轉型作用 8
2.5 過敏原蛋白小量表現測試 9
2.5.1 聚丙烯醯胺膠體電泳 9
2.5.2 西方墨點法 10
2.6 過敏原蛋白大量表現及純化 10
2.6.1 親和性管柱層析 11
2.6.1.1 親和性鈷離子螯合樹脂 11
2.6.1.2 親和性鎳離子螯合樹脂 11
2.6.2 陰陽離子交換管柱層析 11
2.6.2.1 陰離子交換樹脂 12
2.6.2.2 陽離子交換樹脂 12
2.6.3 膠體過濾管柱層析 12
2.6.3.1 HiLoad 16/60 Superdex 75 prep grade 13
2.6.3.2 HiLoad 16/60 Superdex 200 prep grade 13
2.6.4 蛋白質濃度測量 13
2.7 質譜儀鑑定 14
第三章 實驗結果 15
3.1 七種已建立完善純化流程之過敏原蛋白 15
3.1.1 Ara h 1蛋白表現與純化結果 15
3.1.2 Ara h 2蛋白表現與純化結果 15
3.1.3 Art v 1蛋白表現與純化結果 16
3.1.4 Asp f 1蛋白表現與純化結果 16
3.1.5 Pen a 1蛋白表現與純化結果 17
3.1.6 Phl p 1蛋白表現與純化結果 17
3.1.7 Pla a 1蛋白表現與純化結果 17
3.2 尚未建立完善純化流程之過敏原蛋白 18
3.2.1 Hev b 5蛋白表現與純化結果 18
3.2.2 Phl p 5蛋白表現與純化結果 18
3.2.3 Amb a 1蛋白表現結果 19
3.2.4 Cry j 1蛋白表現結果 19
3.2.5 Cry j 2蛋白表現結果 19
3.2.6 Cup s 1蛋白表現結果 19
3.2.7 Gly m 5蛋白表現結果 19
3.2.8 Hev b 6蛋白表現結果 20
3.2.9 Jun a 2蛋白表現結果 20
3.2.10 Par j 2蛋白表現結果 20
3.2.11 Ves v 1蛋白表現結果 20
第四章 討論 21
4.1 不同大腸桿菌菌株造成蛋白質的表現差異 21
4.2 不同質體造成蛋白質的表現差異 21
4.3 過敏原蛋白質純化結果討論 22
4.4 保守區塊和交叉反應的關聯性 22
4.5 生物醫學之相關應用性 23
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