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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 董馨蓮 | |
dc.contributor.author | Yu-Hsuan Yang | en |
dc.contributor.author | 楊育瑄 | zh_TW |
dc.date.accessioned | 2021-06-15T16:11:30Z | - |
dc.date.available | 2020-09-25 | |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-18 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52306 | - |
dc.description.abstract | 瀰漫性大 B 細胞淋巴瘤(DLBCL),根據基因表現可以分為兩大族群。分別為活化型細胞(Activated B-cell like DLBCL, ABC-DLBCL) 與生長中心型細胞(Germinal center B-cell like DLBCL, GCB-DLBCL)。持續活化的NF-κB 路徑活性是維持活化型細胞生存的必要條件。在先前文獻已被報導,CBM (CARMA1-BCL10-MALT1) 複合物中的CARMA1 蛋白突變是造成NF-κB 路徑活化的原因之一。而MALT1 蛋白在活化CBM 複合物與NF-κB 訊息傳遞路徑扮演相當重要的角色。多個研究文獻發現,MALT1 蛋白酶活性(protease activity) 的抑制劑可以有效地殺死活化型細胞,但是相關機制目前仍不清楚。在本篇文章中,將會觀察活化型與生長中心型細胞處理MALT1 抑制劑後,對於NF-κB 路徑的影響。藉此來探討抑制劑殺死活化型細胞的相關機制。由結果中可以觀察到,MALT1 與BCL10的切割產物以及p-IκBα 與IL-6 的產生均只出現在活化型細胞株HBL-1 與OCI-Ly3。這代表著,NF-κB 路徑在活化型細胞中就已經活化了。接著使用MTT 方法測得MALT1 抑制劑(MI-2 z-VRPR-FMK) 以及 IKK 路徑抑制劑(BMS-345541 Bay-11-7085) 在 BJAB 與OCI-Ly3 細胞的IC50 分別為1.54μM、259.7μM、4.22μM 與0.93μM 以及0.58μM、13.76μM、1.45μM 與0.33μM。由此結果得知BAJB 細胞對於這四種NF-κB 路徑抑制劑的耐受性都比OCI-Ly3 細胞來的好。當生長中心型的BJAB 細胞以TPA/Ionomycin 方法刺激NF-κB 路徑活化後,再與活化型OCI-Ly3細胞一樣,被MI-2 藥物處理,都可觀察到BCL10 切割產物消失、IκBα 與 p-IκBα以及IL-6 核醣核酸表現量都下降。若OCI-Ly3 細胞與BJAB 細胞在MALT1knockdown 的處理下,同樣先需使用TPA/Ionomycin 刺激BJAB 細胞的NF-κB路徑活化後,則也可觀察到BCL10 切割產物消失以及IL-6 核醣核酸表現量下降,但是IκBα 與 p-IκBα 表現量並無改變。因此由實驗結果得知,MI-2 藥物處理細胞或是knockdown MALT1 後,確實會使NF-κB 訊息傳遞路徑受到抑制。而我們實驗室認為MI-2 藥物毒殺細胞的可能機制是,MALT1 蛋白酶活性受到抑制後,此蛋白產生dominant negative effect 所導致的現象。 | zh_TW |
dc.description.abstract | Diffuse large B cell lymphoma (DLBCL) can be categorized into two subtypes based on their gene expression patterns. One is activated B-cell like diffuse large B cell lymphoma (ABC type, ABC-DLBCL), the other is germinal center B-cell like diffuse large B cell lymphoma (GCB type, GCB-DLBCL). The NF-κB signaling pathway was constitutively activated in ABC-type DLBCL cells. The activated NF-κB signaling was found to be required for the survival of ABC-type DLBCL cells. Mutation in CARMA1 protein, a recruitment member of CBM (CARMA1-BCL10-MALT1) complex, was previously reported to be involved in the activation of the NF-κB signaling pathway. MALT1, a paracaspase, played an important role in the active CBM complex formation and the activated NF-κB signaling. Several studies reported that proteolytic inhibitors of MALT1 selectively killed the ABC-type DLBCL cells. However, detailed mechanisms mediating the cytotoxic effect of MALT1 inhibitors in ABC-type DLBCL cells were not clear. In this study, molecules in the NF-κB signaling pathway were examined in both ABC- and GCB-type DLBCL cells treated with MALT1 inhibitors to elucidate the possible mechanism(s) mediating the cytotoxic effect in ABC-type DLBCL cells. DLBCL cells with MALT1 knockdown were also included for comparison.The cleavage products of MALT1 and BCL10 , the expression of p-IκBα and IL-6 were present in lysates of HBL1 and OCI-Ly3 cells. The NF-κB signaling pathway was indeed, as reported, activated in these two ABC-type DLBCL cells. MTT assay was utilized to measure IC50 to several cytotoxic agents including two reported MALT1 inhibitors (MI-2,z-VRPR-FMK), two known IKK inhibitors (BMS-345541,Bay-11-7085). BJAB, GCB-type DLBCL cells, was relatively resistant to these NF-κB signaling inhibitors as compared to OCI-Ly3, ABC-type DLBCL cells. TPA/Ionomycin were utilized to stimulate NF-κB signaling in BJAB cells. Pretreatment with MI-2 diminished the appearance of BCL10 cleavage products. Expression levels of p-IκBα and IL-6 were also reduced. Same results were observed in MI-2 treated OCI-Ly3 cells. MALT1 proteolytic activity and IL-6 expression were dampened in TPA/Ionomycin stimulated BJAB cells with MALT1 knockdown as reported. However, expression levels of IκBα and p-IκBα were not affected. Same results were observed in MALT1 knockdown OCI-Ly3 cells. The possible mechanism suggested to be the dominant negative effect of uncleaved MALT1 protein mediating the cytotoxic effect of MALT1 inhibitors in ABC-type DLBCL cells, causing cells to death. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T16:11:30Z (GMT). No. of bitstreams: 1 ntu-104-R02445102-1.pdf: 2082471 bytes, checksum: 2c773981095aac932da1ed59c9297d26 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 口試委員審定書.............................................................................................................i 中文摘要.......................................................................................................................... ii Abstract .......................................................................................................................... iv 目錄................................................................................................................................. vi 圖表目錄......................................................................................................................... ix 第一章、序論.................................................................................................................. 1 一、MALT1 ..................................................................................................................... 1 二、MALT1 會參與在NF-κB 訊息傳遞路徑中,並扮演鷹架蛋白的角色 ............... 1 三、MALT1 的蛋白酶(protease)功能幫助NF-κB 訊息路徑傳遞得更順暢 ............... 2 四、瀰漫性大B 細胞淋巴瘤(Diffuse Large B cell Lymphoma, DLBCL) .................. 4 五、活化型瀰漫性大B 細胞淋巴瘤的存活是需要NF-κB 訊息傳遞路徑持續不斷的 活化著 ....................................................................................................................... 4 六、活化型瀰漫性大B 細胞淋巴瘤細胞株的NF-κB 訊息傳遞路徑持續不斷的活化 是因為基因突變的關係所導致 ............................................................................... 5 七、臨床治療瀰漫性大B 細胞淋巴瘤的治療藥物與方法 ......................................... 6 八、MALT1 抑制劑可用來治療活化型瀰漫性大B 細胞淋巴瘤................................ 6 第二章、材料與方法...................................................................................................... 8 一、細胞培養(Cell culture) ........................................................................................... 8 培養液(Medium) ............................................................................................ 8 細胞株(Cell line) ............................................................................................ 8 冷凍細胞(Frozen Cells) ................................................................................. 9 解凍細胞(Cells Reconstitution) ..................................................................... 9 二、藥物 .......................................................................................................................... 9 vii 【MI-2】 .......................................................................................................... 9 【z-VRPR-FMK】 ........................................................................................... 9 【BMS-345541】 .......................................................................................... 10 【Bay-11-7085】 ........................................................................................... 10 三、抗體 ........................................................................................................................ 10 四、備製慢病毒載體顆粒(Lentiviral Vector Particles Packaging) .............................. 10 五、濃縮慢病毒載體顆粒(Lentiviral Vector Particles Concentration) ........................ 11 六、建立以慢病毒載體系統主導之核糖核酸干擾作用 ............................................ 11 七、建立穩定表現sh-Luc / sh-MALT1 B / sh-MALT1 D 之突變細胞株 .................. 11 八、TPA(12-O-Tetradecanoylphorbol-13-Acetate) / Iomomycin stimulation .............. 12 九、MALT1 抑制劑處理細胞(MALT1 inhibitor treatment) ..................................... 12 十、萃取細胞中的核糖核酸(RNA Extraction) ............................................................ 12 十一、即時聚合酶連鎖反應(Real-Time Polymerase Chain Reaction) ....................... 13 十二、萃取細胞中的蛋白質(Protein Extraction) ........................................................ 13 十三、蛋白質定量分析(Protein Quantification Analysis) ......................................... 13 十四、十二烷基硫酸鈉-聚丙烯醯胺膠體電泳(SDS-PAGE) ................................... 14 十五、蛋白質轉印(Transfer) ........................................................................................ 15 十六、西方墨點分析法(Western Blot Analysis) .......................................................... 15 十七、細胞生長增殖試驗(Cell Proliferation assay) .................................................... 15 十八、抑制50%細胞生長的藥物濃度測定(Drug IC50 Determination) ................... 16 第三章、結果................................................................................................................ 17 一、瀰漫性大B 細胞瘤細胞的NF-κB 路徑活化情形 .............................................. 17 二、MALT1 抑制劑與NF-κB 路徑抑制劑在BJAB 與OCI-Ly3 細胞株的IC50 ..... 18 三、藥物處理後對於BJAB 細胞的NF-κB 路徑活化情形 ....................................... 18 四、BJAB 細胞Knockdown MALT1 後的NF-κB 路徑活化情形 ............................ 19 viii 五、藥物處理後對於OCI-Ly3 細胞的NF-κB 路徑活化情形 ................................... 20 六、OCI-Ly3 細胞Knockdown MALT1 後的NF-κB 路徑活化情形 ....................... 22 第四章、討論................................................................................................................ 23 一、瀰漫性大B 細胞瘤細胞的NF-κB 路徑活化情形 .............................................. 23 二、MALT1 抑制劑與NF-κB 路徑抑制劑在BJAB 與OCI-Ly3 細胞株的IC50 ..... 23 三、探討BJAB 與OCI-Ly3 細胞藥物處理以及MALT1 Knockdown 後對於MALT1 與BCL10 切割產物的影響 ................................................................................... 24 四、探討BJAB 與OCI-Ly3 細胞藥物處理以及MALT1 Knockdown 後對於最下游 產物IL-6 核醣核酸表現量的影響 ........................................................................ 25 五、探討BJAB 與OCI-Ly3 細胞藥物處理後對於IκBα 與p-IκBα 的影響 ........... 25 六、探討BJAB 與OCI-Ly3 細胞MALT1 Knockdown 後對於IκBα 與p-IκBα 的影 響 ............................................................................................................................. 26 七、MALT1 蛋白酶功能以及鷹架蛋白功能對生理機能的貢獻 .............................. 26 第五章、結果圖表........................................................................................................ 28 第六章、附錄圖表........................................................................................................ 36 參考文獻........................................................................................................................ 42 | |
dc.language.iso | zh-TW | |
dc.title | 探討 paracaspase 抑制劑毒殺活化型瀰漫性大B 細胞 淋巴瘤生長的機制 | zh_TW |
dc.title | Mechanism(s) mediating growth inhibition of ABC-DLBCL cells by paracaspase inhibitor. | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳美如,徐立中 | |
dc.subject.keyword | 瀰漫性大B 細胞淋巴瘤,MALT1,MALT1 抑制劑,NF-κB 訊息路徑, | zh_TW |
dc.subject.keyword | Diffuse Large B-Cell Lymphoma (DLBCL),MALT1 Inhibitors,NF-κB Signaling Pathway, | en |
dc.relation.page | 48 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-08-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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ntu-104-1.pdf 目前未授權公開取用 | 2.03 MB | Adobe PDF |
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