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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68776完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林淑華(Shu-Wha Lin) | |
| dc.contributor.author | Chia-Jui Hung | en |
| dc.contributor.author | 洪家瑞 | zh_TW |
| dc.date.accessioned | 2021-06-17T02:34:49Z | - |
| dc.date.available | 2027-08-31 | |
| dc.date.copyright | 2017-09-08 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-17 | |
| dc.identifier.citation | Acke, F.R., I.J. Dhooge, F. Malfait, and E.M. De Leenheer. 2012. Hearing impairment in Stickler syndrome: a systematic review. Orphanet J Rare Dis. 7:84.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68776 | - |
| dc.description.abstract | 先前實驗室建立的 Hepsin 基因剔除小鼠分析後得知其具先天性聽力缺失。為了進一步分析 Hepsin 在聽力扮演的角色，本論文利用先前建立的表達人類野生型 (hHPNWT) 及突變型 Hepsin (hHPNRS) 的基因轉殖鼠，與 Hepsin 基因剔除小鼠配種後所得的子代，作為實驗的研究對象。不同小鼠 Hepsin 背景的轉殖鼠共四種小鼠包括 Tg-hHPNWT68 ; HPN-/- (line68)、Tg-hHPNWT5 ; HPN-/- (line5) 及突變型的 Tg-hHPNRS39 ; HPN-/- (line39)、Tg-hHPNRS54 ; HPN-/- (line54)。首先分析轉基因表現量得知，不論在血漿或肝臟中，皆可測得人類 Hepsin 蛋白質，且 line 68 較 line 5 的表現量高；西方墨點的結果顯示轉基因也表現於小鼠耳蝸中的科蒂氏器 (organ of Corti) 及血管紋 (stria vascularis)。使用腦幹聽性反應 (ABRs) 檢測同窩出生的轉殖基因鼠聽力狀況，結果顯示以野生型小鼠 (HPN+/+) 聽力為對照，Hepsin 基因剔除鼠 (HPN-/-) 聽力最差，Hepsin 表現量較高的基因轉殖小鼠 (Tg-hHPNWT68 ; HPN-/-) 聽力明顯恢復，而表現量較低的小鼠 (Tg-hHPNWT5 ; HPN-/-) 及表現突變型 Hepsin 基因轉殖鼠 (Tg-hHPNRS ; HPN-/-) 則無明顯恢復現象。分析表現人類野生型 Hepsin 小鼠血漿及肝臟中蛋白表現量及聽力的關係，顯示 Hepsin 表現量與聽力呈正相關。
在組織切片中，相對於與 Hepsin 轉殖鼠同窩出生的野生型小鼠頂蓋膜型態緻密且與螺旋緣緊密貼合， Hepsin 基因剔除鼠頂蓋膜異常，與先前文獻發表的一致。表現量較高的轉基因小鼠型態稍有恢復，頂蓋膜空隙較少，然而直接測量頂蓋膜的面積，卻與基因剔除鼠無顯著差異，顯示切片中的頂蓋膜面積大小無法直接反應聽力的狀況。由於耳蝸中轉 (middle turn, MT) 與底轉 (basal turn, BT) 是負責接收高頻 (24k-100k Hz) 聲音的區域，而小鼠是高頻動物，因此分析兩處頂蓋膜的組成分子 type II collagen、type IX collagen、α-tectorin 及 β- tectorin，結果顯示 type IX collagen、α-tectorin 及 β- tectorin 及在基因剔除鼠的頂蓋膜表現量皆明顯下降，包括基因剔除小鼠在中轉及底轉頂蓋膜的 type IX collagen 平均下降為野生型小鼠的 0.6 倍 (n=9) ; α-tectorin平均下降為 0.5 倍, (n=10); β- tectorin 平均下降為 0.75 倍, (n=5)，且實驗得知表現量較高的基因轉殖鼠 (line68) 在中轉及底轉頂蓋膜 type IX collagen 有顯著恢復效果，α-tectorin 則在中轉頂蓋膜有恢復的效果。 由於先前文獻推測，Hepsin 可能影響 α- 及 β-tectorin 的成熟和釋放，本論文推論因 α- 及 β-tectorin 為頂蓋膜膠原纖維間的架橋，缺乏此兩種蛋白穩定頂蓋膜纖維結構可能是導致基因剔除鼠 type IX collagen 表現下降的原因。本論文亦使用基因轉殖鼠證明 Hepsin 確實在聽覺功能扮演重要角色，並發現 Hepsin 缺失致聾的可能機轉，未來可持續探討相關機制，並應用於開發相關的治療藥物。 | zh_TW |
| dc.description.abstract | To investigate the role of Hepsin in the development of hearing and inner ear, my study used the human Hepsin transgenic mice (Tg mice) as models. The Tg mice were crossed to produce four lines for use in the study. The ELISA and Western blot results showed that both the wild-type and mutant form of transgenetic human Hepsin were all detected in plasma and liver. The expression of wild-type Hepsin, line 68, was higher than that of line 5. Moreover, Western blot result showed that human Hepsin could be detected in organ of Corti and stria vascularis in the inner ear, indicating that the human transgene was expressed in the inner ear. Phenotype analysis using auditory brainstem evoked response (ABR) test showed that while the Hepsin-/- mice exhibited profound hearing loss as literally reported, the deafness of high expression mouse line (line 68) were alleviated up to 20 dB SPL. However, the low expression mouse line (line 5) remained serious deafness.
The organ of Corti in cochlea middle and the basal turn is responsible for receiving sound frequency above 24k Hz. Because mice are high frequency animals, the histology analysis in my study focused on the middle and basal turn of cochlea. The H&E stain showed that the anomaly of the tectorial membrane in Tg-hHPNWT68 ; HPN-/- mice were slightly less serious than the HPN-/- mice. Although the hearing threshold had positive correlation with the area, the area of the tectorial membrane had no significant difference. To furthure analyze the components in tectorial membrane, we used the immunofluorescence to quntify molecules mainly expressed on tectorial membrane: alpha tectorin, beta tectorin, type IX collagen, type II collagen of HPN+/+ and HPN-/- mice. The result showed that α-、β-tectorin and type IX collagen were less expressed in HPN-/- mice. In Tg-hHPNWT68 ; HPN-/- mice, the type IX collagen was rescued in all of the middle and basal turn, with α-tectorin only in of the middle turn. According to previous research, α-and β-tectorin may be physiological substrates of Hepsin. As a result, knock out Hepsin might cause the decrease of α-tectorin expression. My study suggested that because α- and β-tectorin are the bridges of collagen in the tectorial membrane, reduced α-tectorin could lead to the unstability of type IX collagen, causing the deformity of tecterial membrane and the deafness. Transgenetic knock-out mice established in our lab was able to study the add-back effect of Hepsin in improving hearing ability. Our results furthure showed that Hepsin indeed plays an important role in hearing, and may help develop therapies on certain patients with congenital hearing loss in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T02:34:49Z (GMT). No. of bitstreams: 1 ntu-106-R04424014-1.pdf: 8196559 bytes, checksum: c2bd66c9be0ef42cbbff73f80c948733 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 中文摘要 I
英文摘要 III 目錄 V 圖目次 VIII 附錄目次 VIII 第一章、緒論 1 前言 1 1.1 Hepsin蛋白結構 1 1.2 Hepsin 體外及體內生理功能 2 1.3 Hepsin 在聽覺的病理角色 3 1.4 聲音傳遞的概觀介紹 4 1.5 耳蝸的構造與功能 5 1.6 科蒂氏器的構造與功能 6 1.7 毛細胞的構造與功能 6 1.8 頂蓋膜的功能與組成 7 1.8.1 頂蓋膜膠原性醣蛋白組成 7 1.8.2 頂蓋膜非膠原性醣蛋白組成 8 研究動機 10 第二章、材料與方法 11 2.1 實驗動物來源及鑑定 11 2.1.1 實驗動物 11 2.1.2 人類 Hepsin基因轉殖小鼠之基因型鑑定 11 2.2 聽力檢測 12 2.2.1腦幹聽性反應 (Auditory Brainstem Responses，ABRs) 12 2.3 檢體處理 12 2.3.1實驗動物犧牲與樣品保存 12 2.3.2 小鼠柯蒂氏器 (Organ of Corti) 及耳蝸血管紋 (stria vascularis) 蛋白萃取 12 2.3.3 小鼠肝臟蛋白質萃取 13 2.3.4 石蠟包埋與切片製作 14 2.3.5 冷凍包埋與切片製作 14 2.4小鼠柯蒂氏器 (Organ of Corti) 及耳蝸血管紋 (stria vascularis) mRNA 萃取與定量 15 2.5 建立酵素連結免疫吸附分析法 15 2.5.1 Hepsin 抗體融合瘤細胞製備 15 2.5.2 篩選高表現量的 Hepsin 抗體融合瘤細胞株 15 2.5.3 限數稀釋單株化Hepsin 抗體融合瘤細胞 16 2.5.4製備大量抗體 16 2.5.5 單株抗體純化 16 2.5.6 酵素連結免疫吸附分析法 17 2.6 西方墨點法 17 2.7 組織染色 18 2.7.1 H&E組織染色 18 2.7.2 全固定(whole mount) 柯蒂氏器 (Organ of Corti) 免疫組織螢光染色 18 2.7.3 免疫組織螢光染色 19 2.7.4 共軛焦顯微鏡拍攝 19 2.8 數據分析與統計 20 第三章、實驗結果 21 3.1 Hepsin 基因剔除鼠聽力功能明顯較野生小鼠差 21 3.2 基因轉殖小鼠人類 Hepsin mRNA表現於內耳 21 3.3 基因轉殖小鼠人類 Hepsin 蛋白質於內耳、血漿及肝臟有表現 21 3.4 人類 Hepsin基因轉殖鼠聽力功能與野生型人類 Hepsin表現量呈正相關 22 3.5 Hepsin基因剔除鼠在耳蝸中轉 (middle turn, MT) 及底轉 (basal turn, BT) 內外毛細胞 (inner and outer hair cell) 型態功能正常 23 3.6 聽神經傳遞功能 23 3.7 直接測量頂蓋膜面積大小無法完全反應聽力的狀況 23 3.8 HPN-/- 小鼠頂蓋膜缺陷與頂蓋膜纖維異常有關 24 3.9 基因剔除鼠與野生鼠在耳蝸中轉 (middle turn, MT) 及底轉 (basal turn, BT) 頂蓋膜的Type II collagen 表現量無差異 25 3.10 基因剔除鼠在耳蝸中轉 (middle turn, MT) 及底轉 (basal turn, BT) 頂蓋膜的Type IX collagen 蛋白表現量較野生型小鼠低，然而在人類 Hepsin 表現量較高的基因轉殖鼠頂蓋膜可看到Type IX collagen 恢復的效果 25 3.11 基因剔除鼠在耳蝸中轉 (middle turn, MT) 及底轉 (basal turn, BT) 頂蓋膜的 α-tectorin 蛋白表現量較野生型小鼠低，然而在人類 Hepsin 表現量較高的基因轉殖鼠頂蓋膜可看到恢復的效果 27 3.12 β-tectorin在耳蝸中轉 (middle turn, MT) 及底轉 (basal turn, BT) 頂蓋膜Hepsin基因剔除鼠 (HPN-/-) 蛋白表現量亦較野生型低 28 第四章、討論 29 4.1 人類 Hepsin 基因轉殖鼠蛋白在不同組織中皆有表現 29 4.2 Hepsin 基因剔除鼠 (HPN-/-) 聽力缺失而基因轉殖鼠聽力明顯獲得改善 29 4.3 內外毛細胞的型態功能正常 30 4.4 基因剔除鼠 (HPN-/-) 頂蓋膜電子顯微鏡分析顯示異常 30 4.5 兩種螢光染色定量分析方式的意義 31 4.6 基因剔除鼠 (HPN-/-) 頂蓋膜分子表現量異常，而基因轉殖鼠有恢復的效果，及其可能的致病機轉 31 第五章、實驗結果及展望 34 參考文獻 35 | |
| dc.language.iso | zh-TW | |
| dc.subject | α-tectorin | zh_TW |
| dc.subject | β-tectorin | zh_TW |
| dc.subject | type IX collagen | zh_TW |
| dc.subject | Hepsin | zh_TW |
| dc.subject | type II collagen | zh_TW |
| dc.subject | Hepsin 基因剔除鼠 | zh_TW |
| dc.subject | 人類 Hepsin 基因轉殖鼠 | zh_TW |
| dc.subject | 內耳頂蓋膜 | zh_TW |
| dc.subject | 聽力缺失 | zh_TW |
| dc.subject | Hepsin | en |
| dc.subject | β-tectorin | en |
| dc.subject | α-tectorin | en |
| dc.subject | type IX collagen | en |
| dc.subject | type II collagen | en |
| dc.subject | tectorial membrane | en |
| dc.subject | hearing loss | en |
| dc.subject | Hepsin transgenic mice | en |
| dc.subject | Hepsin knock-out mice | en |
| dc.title | 探討Hepsin 在小鼠內耳構造及功能扮演的角色 | zh_TW |
| dc.title | Investigating the role of Hepsin in mouse inner ear structure and function | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳瑞菁(Jui-Ching Wu),楊庭華(Ting-Hua Yang),林淑容(Shu-Rung Lin) | |
| dc.subject.keyword | Hepsin,Hepsin 基因剔除鼠,人類 Hepsin 基因轉殖鼠,聽力缺失,內耳頂蓋膜,type II collagen,type IX collagen,α-tectorin,β-tectorin, | zh_TW |
| dc.subject.keyword | Hepsin,Hepsin knock-out mice,Hepsin transgenic mice,hearing loss,tectorial membrane,type II collagen,type IX collagen,α-tectorin,β-tectorin, | en |
| dc.relation.page | 82 | |
| dc.identifier.doi | 10.6342/NTU201703823 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-08-17 | |
| 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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