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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18244完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 康照洲(Jaw-Jou Kang) | |
| dc.contributor.author | Pei-Jun Kao | en |
| dc.contributor.author | 高培鈞 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:56:18Z | - |
| dc.date.copyright | 2015-03-12 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-02-12 | |
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Pancreatic cancers require autophagy for tumor growth. Genes development 25, 717-729. Young-Pearse, T.L., Bai, J., Chang, R., Zheng, J.B., LoTurco, J.J., and Selkoe, D.J. (2007). A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 14459-14469. Yu, W.H., Cuervo, A.M., Kumar, A., Peterhoff, C.M., Schmidt, S.D., Lee, J.H., Mohan, P.S., Mercken, M., Farmery, M.R., Tjernberg, L.O., et al. (2005). Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. The Journal of cell biology 171, 87-98. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18244 | - |
| dc.description.abstract | 克林達黴素為目前廣泛使用於感染症、瘧疾以及青春痘的抗生素，在實驗室前人的研究中發現，克林達黴素會造成細胞中ATP含量下降以及細線體的損傷；這兩個現象均為誘發細胞自噬作用的重要因子。細胞自噬作用為細胞藉由溶酶小體將細胞中非必要物質降解的機制。由於細胞自噬作用為細胞代謝物質的重要機轉，細胞自噬作用在生理上以及病理上扮演重要的角色。另一方面，對於細胞自噬作用的調控可能可以做為新的疾病治療標的或是藥物開發方向。近年的研究發現，阿茲罕默症的重要成因澱粉樣蛋白會經由富含澱粉樣蛋白前驅蛋白(amyloid precursor protein, APP)的器官中，不正常作用的自噬小體及胞吞小體產生。在本篇研究中，我們希望可以探討克林達黴素是否會影響神經膠細胞中的細胞自噬作用，並且進一步探討克林達黴素對於APP生合成或轉移修飾過程造成的影響。結果顯示，在神經膠細胞中投與克林達黴素會造成細胞自噬作用標的蛋白LC3-II/LC3-I的上升，以及造成自噬小體的堆積。比較克林達黴素與細胞自噬作用調控藥物的效果可以發現，克林達黴素會藉由抑制溶小體的活性造成細胞自噬作用的失調。進一步的研究發現，克林達黴素會造成APP朝向non-amyloidogenesis修飾，藉由活化裁切蛋白ADAM10，使得sAPPα上升。透過顯微鏡發現LC3與sAPPα位於相同的位置，且sAPPα將會被細胞自噬作用調控藥物所影響。綜合以上，我們發現在神經膠細胞中，克林達黴素的處理會藉由干擾細胞自噬作用導致sAPPα上升。 | zh_TW |
| dc.description.abstract | Clindamycin is an antibiotic, which is widely used to treat infection, malaria, and acne. In our lab, pervious study has shown that clindamycin treatment would decrease intracellular ATP amount and cause mitochondrial damage, both are important factor in the induction of cell autophagy. Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the actions of lysosomes. Due to the basic and important role of autophagy in protein and organelle degradation, autophagy connects with an astonishing number of human disease and physiology. On the other hand, regulation the autophagy flux in disease may be new treatment target or drug discovery. Recent evidence has shown that the amyloid beta peptide is generated from amyloid beta precursor protein (APP) during autophagy turnover of APP-rich organelles supplied by both autophagy and endocytosis. In this study, we are interested in whether clindamycin would affect glioma cell autophagy, and determent the drug effect on APP expression and trafficking. The result showed clindamycin treatment would induce LC3-II/LC3-I ratio and the autophagosome accumulation. Compare the effect of clindamycin and autophagy regulater show that clindamycin would lead the late stage of autophagy dysfunction through impair lysosome activity. In addition, we found clindamycin would lead Alzheimer’s disease maker protein amyloid precursor protein trafficking to non-amyloidogenesis pathway and up-regulation soluble amyloid precursor protein α(sAPPα) protein level by activated α-secretase, ADAM10 enzyme activity. Use microscopy, we determined LC3 and sAPPα are co-localized, and sAPPα level would regulated by autophagy regulater. Our data suggest that in glioma, clindamycin would up-regulate sAPPα level through autophagy flux impairment. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:56:18Z (GMT). No. of bitstreams: 1 ntu-104-R01447011-1.pdf: 3608885 bytes, checksum: 8135618c81020d1d7f93c4d7e52122ed (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 口試委員會審定書 I 致謝 II 摘要 III Abstract IV 縮寫表 VI 目錄 VII 第一章 1 第一章 緒論 2 1.1. 克林達黴素(clindamycin) 2 1.1.1. 克林達黴素之簡介 2 1.1.2. 克林達黴素於本實驗室之研究 3 1.1.3. 探討克林達黴素新穎功效之可能性 3 1.2. 細胞自噬作用(autophagy) 4 1.2.1. 細胞自噬作用之功能 4 1.2.2. 細胞自噬之機轉 5 1.2.2.1. 起始 5 1.2.2.2. 目標蛋白的辨認 6 1.2.2.3. 自噬小體的形成 6 1.2.2.4. 自噬小體與溶酶小體結合、目標蛋白的降解與釋出 7 1.2.3. 細胞自噬與疾病 8 1.2.3.1 癌症 8 1.2.3.2. 傳染病 9 1.2.3.3. 心血管疾病 9 1.2.3.4. 代謝疾病 9 1.2.3.5. 肺部疾病 10 1.2.3.6. 老化 10 1.2.3.7. 神經退化性疾病 10 1.2.4. 探討細胞自噬作用與澱粉樣蛋白之關聯性 11 1.3. 阿茲罕默症(Alzheimer’s disease) 12 1.3.1. 阿茲罕默症之簡介 12 1.3.2. 澱粉樣蛋白前驅蛋白(amyloid precursor protein，APP) 12 1.3.2.1. APP在體內的分布及異構物 12 1.3.2.2. APP的轉移過程 13 1.3.2.3. APP修飾裁切 13 1.3.2.4. APP的功能 14 1.3.3. 阿茲罕默症與細胞自噬作用 15 1.3.4. 探討藥物影響細胞自噬作用後對於APP蛋白修飾的改變 15 1.4研究動機 16 第二章 23 第二章 材料與方法 24 2.1材料 24 2.1.1細胞株與培養 24 2.1.2藥品與試劑 24 2.1.3抗體與酵素 26 2.1.4質體 27 2.2方法 28 2.2.1細胞存活率試驗 (Cell viability assay) 28 2.2.2西方墨點法 (Western blotting analysis) 28 2.2.3質體轉染 (Plasmid transfect) 29 2.2.4反轉錄聚合酶鏈鎖反應 (reverse transcription-PCR) 29 2.2.5細胞免疫螢光染色法 (Immunofluorescence assay) 31 2.2.6統計分析 31 第三章 32 第三章 結果 33 3.1克林達黴素在神經膠細胞瘤細胞株中促進細胞自噬作用 33 3.1.1 克林達黴素對於神經膠質瘤癌細胞株之細胞存活率影響 33 3.1.2 克林達黴素在細胞中促進細胞自噬標誌蛋白有劑量-效應關係 34 3.1.3 克林達黴素在細胞中促進細胞自噬標誌蛋白有時間-效應關係 34 3.1.4 克林達黴素在細胞中促進酸性小泡的表現 34 3.1.5 克林達黴素在細胞中促進酸性小胞以及自噬小體的表現 35 3.2在神經膠質瘤癌細胞株中克林達黴素投藥促進sAPPα之表現 35 3.2.1 克林達黴素增加細胞內以及細胞外的sAPPα含量 35 3.2.1 克林達黴素在細胞中促進sAPPα具有劑量-效應關係 36 3.2.3 克林達黴素在細胞中促進sAPPα具有時間-效應關係 36 3.2.4 APP mRNA並不會隨著克林達黴素之投藥而上升 37 3.2.5 克林達黴素並不會改變sAPPα的蛋白質穩定性 37 3.3 克林達黴素透過活化α-secretase造成的sAPPα上升 37 3.3.1 克林達黴素活化α-secretase，ADAM10 38 3.3.2 抑制ADAM10後，細胞內及細胞外之sAPPα量受到抑制 38 3.3.3 ADAM10的酵素活性在投與克林達黴素後活化 39 3.4 克林達黴素在細胞中促進sAPPα上升的現象與細胞自噬作用有關 39 3.4.1 克林達黴素在細胞中促進sAPPα與LC3位於相同之位置 39 3.4.2 克林達黴素在細胞中促進sAPPα可以受到細胞自噬抑制劑調控 39 3.4.3 促進細胞中的細胞自噬作用可以反轉克林達黴素所促進的sAPPα上升之現象 41 3.5 克林達黴素在細胞中藉由干擾溶酶小體活性導致細胞自嗜作用失調 42 第四章 44 第四章 討論 45 4.1. 克林達黴素對於阿茲罕默症之應用性 45 4.1.1. 投藥促進的sAPPα對於細胞可能的功能與意義 45 4.1.2. sAPPα量上升與整體APP裁切修飾的關係 47 4.1.3. 神經膠細胞於大腦所扮演之角色與治療潛力 48 4.2 細胞自噬作用在投藥後受到之影響 49 4.2.1. 標誌蛋白的上升與細胞自噬作用後端受到干擾 49 4.2.2. 細胞自噬作用前端抑制劑3-MA 50 4.2.3. 不同的調控藥物與溶酶小體之功能 50 4.2.4. 細胞自噬作用與阿茲罕默症之探討 51 4.3. 克林達黴素之新穎功能 52 4.3.1. 克林達黴素應用於治療的可能性 52 4.3.2. 克林達黴素的效用與前人研究之探討 52 4.3.3. 克林達黴素以及其他具有潛力的阿茲罕默症新藥 53 第五章 54 第五章 結論 55 參考文獻 56 圖表 74 Figure 1.1 The structure of clindamycin. 17 Figure 1.2 The mechanism of clindamycin. 17 Figure 1.3 The catabolic products of the intracellular structures that are targeted by autophagosomes. 18 Figure 1.4 Autophagy and diseases. 18 Figure 1.5 Different types of autophagy. 19 Figure 1.6 Molecular machinery of autophagy. 19 Figure 1.7 Overview of the autophagy pathway. 20 Figure 1.8 APP family and their main domains. 20 Figure 1.9 APP trafficking in neurons. 21 Figure 1.10 Sequential cleavage of the amyloid precursor protein (APP) occurs by two pathways. 21 Figure 1.11 Proposed models of AV accumulation leading to elevated Aβ levels. 22 Figure 2.1. Two different antibodies were used including anti-APP(670-700) polyclonal antibody (the right panel) and mouse anti-APP N-terminal polyclonal antibody (the left panel) on the same sample lysate and showed different molecular weight. 75 Figure 2.2. Western blot by rabbit anti-APP (670-700) polyclonal antibody showed the same molecular weight either sample from medium or lysate. However, western blot by mouse anti-APP N-terminal polyclonal antibody detected different patterns in medium and lysate from the same sample.. 75 Figure 3.1. Clindamycin induced autophagy in treated GBM8401 cell. 79 Figure 3.2. sAPPα expression and secretion level were increased after clindamycin treatment both in cell lysate and culture medium. 84 Figure 3.3. Clindamycin-enhanced sAPPα correlated with the enhanced enzyme activity of α-secretase, ADAM10. 87 Figure 3.4. Clindamycin-enhanced sAPPα was involve in autophagy flux. 91 Figure 3.5. Clindamycin impaired autophagy flux as well as Baf A1. 92 Figure 5.1. Clindamycin treatment enhanced sAPPα expression through autophagy-dependent pathway 93 Figure 5.2. Proposed mechanism: The involvement of autophagy during APP trafficking.......................................................................................................94 | |
| dc.language.iso | zh-TW | |
| dc.title | 克林達黴素透過干擾細胞自噬作用誘發可溶性澱粉樣蛋白前驅蛋白-α表現 | zh_TW |
| dc.title | Clindamycin Upregulated Soluble Amyloid Precursor Protein α Through Autophagy Flux Impairment | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 孔繁璐(Fan-Lu Kung),鄭幼文(Yu-Wen Cheng) | |
| dc.subject.keyword | 克林達黴素,細胞自噬作用,阿茲罕默症,澱粉樣蛋白前驅蛋白,可溶性澱粉樣蛋白前驅蛋白-alpha, | zh_TW |
| dc.subject.keyword | clindamycin,autophagy,alzheimer’s disease,amyloid precursor protein,sAPPα, | en |
| dc.relation.page | 94 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2015-02-12 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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