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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林敬哲(Jing-Jer Lin) | |
| dc.contributor.author | Rong-Chi Hu | en |
| dc.contributor.author | 胡容綺 | zh_TW |
| dc.date.accessioned | 2021-06-08T01:41:45Z | - |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-19 | |
| dc.identifier.citation | Hayflick L, Moorhead PS: The serial cultivation of human diploid cell strains. Exp Cell Res 1961, 25:585-621.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18991 | - |
| dc.description.abstract | 人體中大部分的正常體細胞無法無限制地進行細胞分裂，並最終會進入不可逆的生長停止階段，稱之為細胞老化。雖然目前已經有研究發現端粒縮短(telomere shortening)為誘發老化的主因，但仍有許多調控和維持細胞老化過程的未知因子。絲氨酸水解酶在人體蛋白質中佔了約1%的含量，且許多絲氨酸水解酶參與在重要的生理作用中，除此之外，許多絲氨酸水解酶被發現會影響細胞老化，所以本研究的目的為尋找會參與在老化過程的絲氨酸水解酶並進一步研究其特性。本研究利用以活性為基礎的化學蛋白質體分析方法，來鑑定在老化過程中活性有改變的絲氨酸水解酶。在本研究中，利用人類肺纖維母細胞IMR90作為研究細胞老化的平台，並以擁有ethyl-benzylphosphonofluoridates反應端的化學探針LCL08027來標定具有活性的絲氨酸水解酶。透過比較年輕和老化細胞中標定蛋白的差異，鑑定到一些絲氨酸水解酶在老化過程中會有活性的改變，其中tripeptidyl peptidase 2 (TPPII)和protein phosphatase methylesterase 1 (PPME1)的活性會隨著老化而降低。進一步利用small hairpin RNAs發現，當抑制TPPII和PPME1的基因表現時會誘導年輕的IMR90細胞進入老化，證實了這兩個絲氨酸水解酶會參與在老化過程中。總結以上，本研究成功利用以活性探針為基礎的蛋白質體分析法去鑑定到尚未被證明會被參與在老化過程的絲氨酸水解酶。 | zh_TW |
| dc.description.abstract | Most of normal human somatic cells cannot divide indefinitely and eventually enter a state of irreversible proliferative arrest termed replicative senescence. Although previous researches have shown that telomere shortening is the major reason for inducing senescence in human somatic cells, factors that mediate and maintain senescence are largely unknown. Serine hydrolases is a large enzyme family which constitutes about 1% of the human proteome and many of them are involved in important physiological processes. In addition, many serine hydrolases have been shown to affect cellular senescence. Thus, the goal of this research is to identify and characterize novel serine hydrolases that participate in senescence. An activity-probe based chemical proteomic approach was applied to identify serine hydrolases with their activities been altered during senescence. Here the human lung fibroblast IMR-90 cell was used as a model in this research. Chemical probe LCL8027, which has an ethyl-benzylphosphonofluoridates reactive group, is used to label active serine hydrolases. Through comparative labeling of both young and old cells, several serine hydrolases were identified that showed alteration of labeling activities during senescence. Among them, both the activities of tripeptidyl peptidase 2 (TPPII) and protein phosphatase methylesterase 1 (PPME1) were found to be decreased during senescence. Further analyses showed that knocking down TPPII or PPME1 using small hairpin RNAs induced young IMR90 cells into senescence, suggesting a role of these two serine hydrolases in senescence. Together, this study successfully applied an activity probe-based proteomic analysis to identify novel serine hydrolases that might be involved in cellular senescence. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T01:41:45Z (GMT). No. of bitstreams: 1 ntu-105-R03442009-1.pdf: 4826931 bytes, checksum: 7d7b51ba2d65ad83f7b233d56fbce886 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 目錄
目錄 i 表目錄 iii 圖目錄 iv 縮寫檢索表 v 摘要 vii Abstract viii 第一章 緒論 1 1.1 細胞老化 (Cellular senescence) 1 1.1.1 複製老化 (Replicative senescence) 2 1.1.2 壓力所誘發之老化 (Stress-induced senescence) 2 1.2 絲氨酸水解酶 (Serine hydrolases) 3 1.3 蛋白質表現量與活性之監測 4 1.4 化學活性探針 (Activity-based chemical probe) 5 1.5 以Fluorophosphonate (FP)為反應端之化學活性探針 6 1.6 利用活性探針尋找參與在細胞老化中的絲氨酸水解酶 6 第二章 材料方法 8 2.1 細胞株培養 8 2.1.1 細胞株之培養 8 2.1.2 細胞株的來源與細胞培養液 8 2.2 細胞計數 8 2.3 生長曲線 (Population doubling curve) 9 2.4 蛋白質樣品處理與濃度測定 9 2.4.1 蛋白質樣品處理 9 2.4.2 蛋白質濃度測定 9 2.5 西方墨點法 (Western blotting analysis) 9 2.5.1 SDS聚丙烯醯胺凝膠電泳 (SDS-PAGE) 9 2.5.2 轉漬 (Transfer) 10 2.5.3 免疫轉漬分析 (Immunoblot) 10 2.6 考馬斯藍染色法 (Coomassie blue staining) 11 2.7 化學探針標定反應 11 2.7.1 LCL08027探針標定濃度測試 11 2.7.2 PD-10脫鹽管柱去除未反應LCL08027探針 11 2.7.3 LCL08027探針標定蛋白質之純化 11 2.8 液相層析串聯式質譜儀分析、蛋白身分鑑定及相對定量 12 2.8.1 質譜樣品前處理 12 2.8.2 液相層析串聯式質譜(LC-MS/MS)分析與蛋白身分鑑定及定量 13 2.9 大腸桿菌勝任細胞 (competent cells) 菌株與製備 13 2.9.1 菌株 13 2.9.2 製備 13 2.10 質體之來源、製備與轉殖作用 14 2.10.1 質體之來源 14 2.10.2 質體之製備 (Geneaid, PrestoTM mini plasmid kit) 14 2.10.3 轉殖作用 (Transformation) 14 2.11 轉染作用 (Transfection) 與慢病毒的製備 (Lentivirus production) 15 2.12 慢病毒效價測定 (Lentivirus determination) 15 2.13 免疫沉澱法 (Immunoprecipitation) 16 2.14 Senescence-associated beta-galactosidase staining 16 2.15 溴化去氧尿苷 (BrdU) 與免疫螢光染色 (Immunofluorescent staining) 16 2.16 全部訊息核糖核酸萃取與反轉錄聚合酶連鎖反應 (Reverse transcription-polymerase chain reaction; RT-PCR) 17 2.16.1 萃取全部訊息核糖核酸 17 2.16.2 反轉錄反應 (Reverse transcription) 18 2.17 即時定量聚合酶連鎖反應 (Real-time quantitative polymerase chain reaction；RT-Q-PCR) 18 第三章 實驗結果 19 3.1 分析IMR90細胞的老化現象 19 3.2 LCL08027探針標定IMR90細胞蛋白質萃取液之濃度探討 19 3.3 使用PD-10脫鹽管柱去除未反應探針之基本實驗條件探討 20 3.4 分析年輕細胞與老化細胞中絲氨酸水解酶之差異 21 3.5 利用蛋白質譜鑑定LCL08027探針標定之絲氨酸水解酶 21 3.6 利用西方墨點法確認特定蛋白標定的結果 22 3.7 利用免疫沉澱法分離絲氨酸水解酶進行分析 23 3.8 降低TPPII基因的表現導致IMR90細胞走向老化 24 3.9 降低PPME1基因的表現導致IMR90細胞走向老化 25 第四章 討論 26 參考文獻 33 表目錄 Tabel 1. shRNAs from National RNAi Core Facility 39 Tabel 2. Compare serine hydrolases between young and old IMR90 cell from mass spectrometry data 40 Tabel 3. Biological process of identified serine hydrolases by Ingenuity Pathway Analysis. 43 圖目錄 Figure 1. Structure and labeling mechanism of LCL08027. 44 Figure 2. Senescence phenotype of IMR90 cells. 45 Figure 3. Titration of LCL08027 probes in IMR90 cell lysates. 46 Figure 4. Schematic presentation of activity probe-based proteomic analysis using LCL08027. 47 Figure 5. Elution of probe-labeled proteins from PD-10 column. 48 Figure 6. Differences of probe-labeled serine hydrolases in young and old IMR90 cells. 49 Figure 7. Mass spectrometry analysis of probe-labeled serine hydrolases in young and old IMR90 cells. 50 Figure 8. The labeling of TPPII, TPPI, and PPME1 are altered in young and old IMR90 cells. 51 Figure 9. Schematic presentation of approach used to detect specific serine hydrolase activity. 52 Figure 10. Alteration of TPPII, PPME1, and TPPI activities during senescence. 54 Figure 11. The expression levels of TPPI, TPPII and PPME1 in young and senescent IMR90 cells. 55 Figure 12. Knock down TPPII in IMR90 cells caused senescence phenotype. 57 Figure 13. Knock down TPPII in IMR90 cells caused cell growth arrest. 60 Figure 14. Knock down PPME1 in IMR90 cells caused senescence phenotype. 61 Figure 15. Knock down TPPII in IMR90 cells caused cell growth arrest. 62 | |
| dc.language.iso | zh-TW | |
| dc.title | 利用化學探針尋找參與在老化過程中的絲氨酸水解酶 | zh_TW |
| dc.title | Identification and Characterization of Serine Hydrolases in Senescence Using Chemical-based Proteomic Approach | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 羅禮強(Lee-Chiang Lo),林照雄(Chao-Hsiung Lin) | |
| dc.subject.keyword | 細胞老化,絲氨酸水解?,化學探針, | zh_TW |
| dc.subject.keyword | cellular senescence,serine hydrolases,chemical-based proteomic approach,activity-based probe, | en |
| dc.relation.page | 62 | |
| dc.identifier.doi | 10.6342/NTU201603370 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2016-08-19 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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