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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 林淑華(Shu-Wha Lin) | |
dc.contributor.author | Chia-Lun Hong | en |
dc.contributor.author | 洪嘉倫 | zh_TW |
dc.date.accessioned | 2021-06-16T02:27:44Z | - |
dc.date.available | 2018-09-25 | |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-04 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53692 | - |
dc.description.abstract | 內皮唾酸蛋白質自1992 年被發現在許多人類腫瘤樣本會高量表現並被鑑定為一腫瘤內皮細胞的表面特異性抗原。此蛋白質的表現位置原本被認為是腫瘤血管內皮細胞,但最新的細胞共位研究皆顯示其表現細胞並非血管內皮細胞,而是在腫瘤相關周細胞、肌纖維母細胞。雖然內皮唾酸蛋白質很早即被發現在許多人類腫瘤基質組織會表現,但目前為止,其在腫瘤進程扮演的角色仍不清楚。本論文的目標在探討內皮唾酸蛋白質在肺腫瘤生長進程的功能。為此,我設計了內皮唾酸蛋白質基因剔除小鼠模型(分別是在C57BL/6J 與NOD.SCID 基因背景),並鑲嵌半乳醣苷酶報導基因,此報導基因受內源性內皮唾酸蛋白質啟動子調控,藉此模擬肺腫瘤內皮唾酸蛋白質的表現模式。我以正位肺腫瘤移植小鼠模型做為研究內皮唾酸蛋白質功能的工具,藉由上述基因剔除小鼠模型的設計,分別進行小鼠/人類來源肺癌細胞株的接種實驗,透過此肺腫瘤模型可以幫助追蹤內皮唾酸蛋白質在生長進程的表現模式以及鑑定表現細胞類型。從實驗結果來看,內皮唾酸蛋白質缺乏小鼠的肺腫瘤重量比、最大直徑都比野生型、異型合子小鼠的腫瘤小,且肺腫瘤組織的血管內皮細胞數量也較少。由結果推測內皮唾酸蛋白質的缺乏是造成上述現象的原因,並進一步假設此蛋白質的功能是促進肺腫瘤的成長。相較於正常肺組織,肺腫瘤的內皮唾酸蛋白質的表現明顯被激發,數據顯示表現此蛋白質的細胞數目增加幅度約十倍,且其表現量和對偶基因數目成正比。在表現細胞類型的鑑定,我以免疫螢光染色共位分析,確認內皮唾酸蛋白質在小鼠肺腫瘤模型的表現細胞類型是周細胞,不是血管內皮細胞。以基因剔除小鼠進行肺腫瘤移植的實驗結果看到,內皮唾酸蛋白質缺乏小鼠的腫瘤相關周細胞明顯比野生型與異型合子少。將周細胞分為第一、第二型子群分析,內皮唾酸蛋白質缺乏小鼠腫瘤得這兩群周細胞的數目也是呈現減少的趨勢,尤其是與血管新生相關的第二型周細胞減少了50%。為了驗證內皮唾酸蛋白質對腫瘤血管新生的影響,我以流式細胞儀分選出肺腫瘤表現內皮唾酸蛋白質的細胞,並以管柱生成實驗分析跟血管內皮細胞形成血管管柱的能力。體外試驗的結果發現,內皮唾酸蛋白質缺乏會造成周細胞管柱形成能力下降,包括所有觀察指標:管柱長度、管柱分叉數和管柱交會點,其下降幅度最大為50%,顯示此蛋白質對於維持腫瘤血管新生的重要性。總結來看,本論文以半乳醣苷酶報導基因取代內皮唾酸蛋白質基因,建構一基因剔除小鼠,在此小鼠的肺腫瘤正位移植模型顯示,內皮唾酸蛋白質缺乏會造成腫瘤生長進程變慢、血管內皮細胞數變少、周細胞數目下降(包括第一型、第二型周細胞子群)、管柱形成能力降低。在基因剔除小鼠觀察到的這些表現型的改變,顯示內皮唾酸蛋白質在肺腫瘤成長進程扮演重要的角色,關於此蛋白質在細胞訊息傳遞路徑所處的位置則仍待未來進一步鑑定。 | zh_TW |
dc.description.abstract | Endosialin was first characterized as a tumor endothelial marker (TEM1) in several human cancer specimens in 1992. Its expression was initially considered in tumor endothelial cells. It was until recently that the endosialin-expressing cell types of endosialin were finally proved to be tumor associated pericytes and fibroblasts but not endothelial cells by several research groups. Although endosialin was discovered in cancer stroma, its role in cancer progression is still not clear. In this study, we aimed to investigate the function of endosialin-expressing cells during cancer progression in the lung. For this purpose, we generated two endosialindeficient mouse models (C57BL/6J and NOD.SCID genetic background) with the lacZ reporter gene under the control of the endosialin promoter. In such endosialin-deficient mouse models, we transplanted mouse/human lung tumor cells into endosialin-deficient
mouse line to dissect its role in tumor progression. Such an orthotopic lung tumor transplantation method in the endosilain-lacZ mice allowed us to trace the location of endosialin-expressing cells in the lung tumors after two weeks of tumor inoculation. The data indicated that in the endosialin-deficient mice, both the size of lung tumors and the number of CD31-positive cells (endothelial cells) in tumors were smaller than those in wild-type and heterozygous mice, suggesting that endosialin deficiency may be responsible for the reduction of the tumor vessels that are required to support tumor growth. In addition, the number of endosialin-lacZ-expressing cells, which was in proportion to the lacZ copy number, increased in the tumors compared to non-tumor parts in both heterozygous and homozygous mice. Moreover, we found that the number of pericytes (marked by either NG2 or desmin) decreased in the endosialin-deficient mice compared to those in the wild-type and heterozygous mice. In tube formation assay, endosialin-deficient pericytes have lower tube-forming ability when compared to those with endosialin expression. Endosialin-deficient pericytes showed decreased total tube length, tube junctions and branch points when interact with endothelial cells, indicated that endosialin may play an important role in tumor angiogenesis. In summary, we found that endosialin expression was quiescent in the normal adult mouse lung but the expression was induced dramatically during lung tumor progression. More importantly, we found that lack of endosialin decreased the numbers of both type I and type II pericytes in tumors. The isolated lung tumor endosialin-deficient pericytes also showed decreased angiogenic ability when coculture with endothelial cells. Such changes may be causally linked to the decrease of tumor vessels and the reduction of tumor size seen in endosialin-deficient mice. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T02:27:44Z (GMT). No. of bitstreams: 1 ntu-104-D97424005-1.pdf: 11024083 bytes, checksum: d7feea02ab04cd262191673652c02695 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 口試委員會審定書……………………………………………………………………..i
誌謝……………………………………………………………………………………..ii 中文摘要………………………………………………………………………………..iii Abstract……...…………………………………………………………………………..v 第一章 序論………………………………………………………………………..…...1 1.1 內皮唾酸蛋白質的發現 …………………………………………….…..…...1 1.2 內皮唾酸蛋白質基因與結構組成……………………………………….…...1 1.3 內皮唾酸蛋白質在腫瘤組織的表現模式………………………………..…..2 1.4 正常生理的內皮唾酸蛋白質表現模式……………………..………………..4 1.5 內皮唾酸蛋白質在肺癌生長進程扮演的角色…………………………..…..5 1.6 周細胞在腫瘤血管新生扮演的角色…………………………………….…...6 1.7 內皮唾酸蛋白質參與的訊息傳遞路徑……………………………...……….8 1.8 重要性 (Significance)………………………………………………..….……9 1.9 研究目標(Specific aims)………………………………………………………11 1.10 實驗設計與策略………………………………………………………..……13 1.11 實驗成果概述……………………………………………………………..…15 第二章 實驗材料與方法……………………………………………………………….19 2.1 實驗材料………………………………………………………………………19 2.2 產製鑲嵌半乳糖苷酶的內皮唾酸蛋白質基因剔除小鼠……………………19 2.3 以南方墨點法確認內皮唾酸蛋白質基因剔除小鼠性腺傳承能力…………20 2.4 小鼠DNA萃取與基因型鑑定…………………………………………………21 2.5 β-半乳醣苷酶染色 ……………….………..………………………………….22 2.6 石蠟包埋與切片……………………………………………………………….23 2.7 正位移植肺癌細胞至內皮唾酸蛋白質基因剔除小鼠左肺………………….23 2.8 非侵入式活體影像系統分析肺腫瘤………………………………………….24 2.9 蛋白質萃取與西方墨點法…………………………………………….………25 2.10 肺腫瘤切片蘇木紫和伊紅染色…………………………………….……….26 2.11 石蠟切片免疫螢光染色……………………………………………………..26 2.12 石蠟切片免疫組織化學染色………………………………………………..27 2.13 肺腫瘤冷凍切片處理………………………………………………………..28 2.14 冷凍切片免疫螢光染色……………………………………………………..28 2.15 共軛焦顯微鏡影像系統……………………………………………………..29 2.16 以流式細胞分選儀篩選周細胞……………………………………………..29 2.17 以FDG篩選表現β-半乳醣苷酶的細胞……………………………………30 2.18 管柱形成(Tube formation)實驗…………………………………………..….30 2.19 以Angiosys軟體分析管柱形成能力……………………………………….31 2.20 數據分析與統計……………………………………………………………..32 第三章 實驗結果……………………………………………………………………….33 3.1 產製內皮唾酸蛋白質基因剔除小鼠…………………………………...…….33 3.2 內皮唾酸蛋白質在小鼠發育過程的表現模式………………………………34 3.3 內皮唾酸蛋白質在小鼠發育過程的各主要器官組織表現情形……………34 3.4 路易斯氏肺腫瘤正位移植小鼠模型……………………………………..…..35 3.5 小鼠肺腺瘤細胞株TC-1正位移植小鼠模型…………………………….….39 3.6 人類肺癌細胞株在免疫不全小鼠的正位移植模型………………………....41 3.7 肺腫瘤組織表現內皮唾酸蛋白質的細胞類型………………………………41 3.8 針對路易斯氏肺腫瘤表現內皮唾酸蛋白質的周細胞進行分群……………42 3.9 內皮唾酸蛋白質在第二型周細胞子群表現的比例…………………………43 3.10第一型周細胞在基因剔除小鼠肺腫瘤的組成…………….………………..44 3.11 篩選並分析肺腫瘤表現內皮唾酸蛋白質的細胞行為特性………………..45 第四章 討論……………………………………………………..………….……...…...47 4.1 產製內皮唾酸蛋白質基因剔除小鼠策略……………………………………47 4.2 內皮唾酸蛋白質在小鼠發育過程的表現模式………………………………47 4.3 內皮唾酸蛋白質對路易斯氏肺腫瘤生長的影響……………………………48 4.4 內皮唾酸蛋白質在小鼠肺腫瘤的表現細胞類型……………………..……..49 4.5 內皮唾酸蛋白質對於肺腫瘤第一、二型周細胞子群的影響………….…...50 4.6 分析肺腫瘤表現內皮唾酸蛋白質細胞的行為特性……………………...….52 第五章 結論與展望…………………………………………………………………….53 參考文獻………………………………………………………………………………...55 圖. ……………………………………………………………………………………….64 表. ………………………………………………………………………………………105 附錄…………………………………………………..…………………………………109 | |
dc.language.iso | zh-TW | |
dc.title | 探討內皮唾酸蛋白質在肺癌的角色 | zh_TW |
dc.title | Dissecting the role of endosialin in lung cancer | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 吳華林(Hua-Lin Wu),張育嘉(Yu-Jia Chang),楊雅倩(Ya-Chien Yang),俞松良(Sung-Liang Yu),黃祥博(Hsiang-Po Huang) | |
dc.subject.keyword | 內皮唾酸蛋白質,基因剔除小鼠,正位肺腫瘤移植,周細胞,血管新生, | zh_TW |
dc.subject.keyword | Endosialin,gene knock out mouse,orthotopic lung tumor transplantation,pericytes,angiogenesis, | en |
dc.relation.page | 110 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-08-04 | |
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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