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  1. NTU Theses and Dissertations Repository
  2. 醫學院
  3. 微生物學科所
Please use this identifier to cite or link to this item: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/9104
Full metadata record
???org.dspace.app.webui.jsptag.ItemTag.dcfield???ValueLanguage
dc.contributor.advisor董馨蓮(Shin-Lian Doong)
dc.contributor.authorSu-Hsin Tsangen
dc.contributor.author臧素心zh_TW
dc.date.accessioned2021-05-20T20:09:22Z-
dc.date.available2019-07-27
dc.date.available2021-05-20T20:09:22Z-
dc.date.copyright2009-09-15
dc.date.issued2009
dc.date.submitted2009-07-30
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dc.identifier.urihttp://tdr.lib.ntu.edu.tw/jspui/handle/123456789/9104-
dc.description.abstract轉錄因子NF-κB是調控淋巴球的活化中最主要的角色,其作用包括促進淋巴球的增生、分化以及細胞激素的製造。近年來的研究陸續指出,CBM complex(CARMA1-BCL10-MALT1)參與調控抗原受體活化NF-κB的路徑中。在實驗室先前的研究與Rebeaud, F. et al. (2008)的研究中,發現在淋巴球活化後,BCL10有被誘導切割的現象,而這個動作可能是透過類似caspase的para-caspase MALT1所造成。除了淋巴球之外,最近也有許多研究陸續證明CBM complex也參與在一些ITAM(immunoreceptor tyrosine-based activation motif)-containing receptor、TLR(Toll-like receptor)或GPCR(G protein-coupled receptors)所活化的NF-κB路徑中,雖然越來越多的研究探討BCL10在NF-κB活化路徑的調控,但對於BCL10切割的機制或者是否還有其他生理上的意義上的研究則付之闕如。因此我們試圖建立不同細胞活化NF-κB的模組,想要知道其他細胞活化NF-κB的路徑是否也有CBM complex的參與,並且觀察BCL10是否有發生被誘導切割的現象,來找出BCL10切割的機制以及其在生物中意義。
我的研究方法是利用各種刺激物(PMA/ionomycin、TNF-α、LPS、zymosan、IL-1β、Helicobacter pylori)來刺激不同細胞(淋巴系細胞:Jurkat 、Raji、Akata、NK,骨髓系細胞:Raw264.7、THP-1,非血球系細胞:HeLa、AGS、293T)用以活化NF-κB。我們以IκBα的降解以及冷光酵素測定法觀察NF-κB活化的狀況,並以免疫沈澱法將BCL10沈澱下來再以磷酸水解酶處理,觀察BCL10切割的情形。當刺激物活化NF-κB路徑,但不見BCL10的變化時,使用核酸干擾BCL10來驗證BCL10是否參與在活化路徑中。最後再以NF-κB抑制劑(MG132、Bay11-7085)以及鈣離子螯合劑(BAPTA-AM),在Jurkat細胞中觀察對BCL10切割的影響,找出調控BCL10切割的因子。
本研究結果發現BCL10的切割只發生在T細胞、B細胞以及自然殺手細胞中,而TNF-α及IL-1β所誘導的NF-κB活化路徑中不需要BCL10的參與。雖然BCL10-MALT1存在於許多細胞中,但是MALT1在NF-κB活化時所誘導BCL10的切割卻不是一個共通的現象,顯示此切割的行為還需要MALT1以外的因子參與。當我們將Jurkat細胞以NF-κB抑制劑前處理後,再以PMA/ionomycin刺激,發現經MG132(抑制IκBα的降解)前處理之後並不影響BCL10的切割,但是經Bay11-7085(抑制IκBα的磷酸化)前處理過後的細胞,其BCL10的切割有被抑制的現象,顯示IKK的活性可能是造成BCL10切割的原因。最後我們以鈣離子螯合劑(BAPTA-AM)使細胞內鈣離子濃度降低,可以發現NF-κB的活化以及BCL10的切割有被抑制的情況,顯示鈣離子可以幫助BCL10的切割以及NF-κB的活化。
由於不同細胞以不同的CARD-containing adaptor組合成CBM complex來活化NF-κB的路徑(例如T細胞、B細胞以及NK細胞所使用的是CARMA1,骨髓系細胞所使用的是CARD9),因此BCL10的切割可能與CARMA1的選用有關。CRAMA1與CARD9在蛋白質構造上的差異在於CARD9缺少了linker以及MAGUK domain,這個差異性使CARD-containing adaptor在活化上的調控有很大的不同,而這個調控的不同可能就是造成BCL10切割與否的關鍵。先前在實驗室的研究顯示磷酸化的BCL10更容易被MALT1所誘導切割,在Zeng, H. et al.(2007)的研究也指出IKKβ具有將BCL10磷酸化的能力,進而使之降解而抑制NF-κB的活化。因此我們推論,BCL10切割的機制可能與調控CARMA1-BCL10-MALT1 complex的活化有關,透過CBM complex活化IKK complex後,以IKKβ的活性將BCL10磷酸化而使之造成切割的結果,而鈣離子可能透過某種機制協助參與切割的調控當中,至於BCL10切割在生物中所扮演的角色仍是值得繼續探討的部分。
zh_TW
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Previous issue date: 2009
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dc.description.tableofcontents目錄
口試委員審定書……………………………………………………………………Ⅰ
中文摘要……………………………………………………………………………Ⅱ
英文摘要……………………………………………………………………………Ⅴ
第一章、 序論…………………………………………………………………… 1
1.1 CBM complex個論…………………………………………………… 1
1.2 CBM complex在後天免疫訊息傳遞中的角色……………………… 8
1.3 CBM complex在先天免疫以及非免疫的訊息傳遞………………… 10
第二章、 研究目的……………………………………………………………… 11
第三章、 材料與方法…………………………………………………………… 12
第四章、 結果…………………………………………………………………… 21
4.1 建立各種細胞活化NF-κB路徑的模組……………………………… 21
4.1.1 淋巴球系血球細胞……………………………………………… 21
4.1.2 骨髓系血球細胞………………………………………………… 22
4.1.3 非血球系細胞…………………………………………………… 23
4.1.4 自然殺手細胞…………………………………………………… 24
4.2 BCL10切割的機制…………………………………………………… 24
4.2.1 IKK的活性參與BCL10切割的機制…………………………… 24
4.2.2 鈣離子(Calcium)參與BCL10切割的機制……………………… 25
 
第五章、 討論…………………………………………………………………… 27
5.1 BCL10的切割需要MALT1以及額外因子的參與…………………… 27
5.2 CARMA1-BCL10-MALT1的選用可能是造成切割的原因………… 27
5.3 CARD domain的遮蔽造成選用的差異………………………………...30
5.4 CARMA1與CARD9的功能性比較………………………………… ..30
5.5 IKK對於BCL10切割的重要性……………………………………… .31
5.6 BCL10切割的功能與意義………………………………………………32
第六章、 參考文獻……………………………………………………………… .33
圖表…………………………………………………………………………………41
附圖………………………………………………………………………………….56
dc.language.isozh-TW
dc.titleBCL10切割機制之探討zh_TW
dc.titleInvestigation on the Mechanisms of BCL10 cleavageen
dc.typeThesis
dc.date.schoolyear97-2
dc.description.degree碩士
dc.contributor.oralexamcommittee李財坤(Tsai-Kun Li),陳青周(Ching-Chow Chen)
dc.subject.keywordCARMA1,CARD9,BCL10,MALT1,NF-κB活化,zh_TW
dc.subject.keywordCARMA1,CARD9,BCL10,MALT1,NF-κB activation,en
dc.relation.page59
dc.rights.note同意授權(全球公開)
dc.date.accepted2009-07-30
dc.contributor.author-college醫學院zh_TW
dc.contributor.author-dept微生物學研究所zh_TW
Appears in Collections:微生物學科所

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