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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 江伯倫(Bor-Luen Chiang) | |
| dc.contributor.author | Szu-Ying Chen | en |
| dc.contributor.author | 陳思縈 | zh_TW |
| dc.date.accessioned | 2021-05-20T21:34:33Z | - |
| dc.date.available | 2020-08-17 | |
| dc.date.available | 2021-05-20T21:34:33Z | - |
| dc.date.copyright | 2010-09-09 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-17 | |
| dc.identifier.citation | Allman, D., and Pillai, S. (2008). Peripheral B cell subsets. Curr Opin Immunol 20, 149-157.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10501 | - |
| dc.description.abstract | 全身紅斑性狼瘡是一全身性自體免疫疾病，其致病機轉是多因子的，包含遺傳基因、性荷爾蒙、環境及許多異常之免疫因素。其中B細胞過度活化被認為在狼瘡的致病機轉中扮演一個重要的角色，而其中B-1細胞又被認為與自體抗體的發生有關。先前研究顯示移除腹腔之B-1細胞，可以有效改善疾病的惡化。然而，這些方式可能產生後續不良的副作用。p110δ是PI3Ks家族中具白血球專一性之催化性次單元，已被證實可去除成熟之B細胞，特別是marginal zone B細胞和B-1細胞之族群。因此本研究想藉由一專一性抑制p110δ之藥物IC87114抑制p110δ的作用，來干擾全身紅斑性狼瘡NZB/W F1小鼠腹腔中過度活化之B-1細胞的數量，以緩解疾病的發展，並且研究此抑制劑在生物體內與體外的作用。首先在細胞實驗裡，我們發現使用高、低劑量的IC87114可以降低脾臟細胞、B-1與B-2細胞的增生作用，亦可降低腹腔細胞與B-1細胞分泌IL-10的能力；而更進一步使用高、低劑量的IC87114對Balb/c小鼠進行腹腔注射後，發現小鼠不論腹腔和脾臟中B、T細胞的數量與活化程度皆不受影響，但高劑量的IC87114對小鼠腹腔細胞的增生具有抑制作用。而在狼瘡小鼠的動物實驗中，我們在小鼠第二個月開始腹腔注射IC87114，可以發現小鼠在第四個月齡，低劑量的IC87114與wortmannin治療組和發病組相比較，其血清中anti-ss/dsDNA IgG自體抗體有顯著性的降低。綜合以上實驗結果可以發現，p110δ抑制劑確實可以有效抑制B細胞在增生與分泌IL-10上之功能，但並不會影響小鼠體內免疫細胞之數量、活化程度，以及免疫細胞的族群分布。而相關研究應用在狼瘡小鼠模式上也可證實早期給予p110δ抑制劑干擾可以有效降低小鼠體內自體抗體的表現，顯示針對PI3Ks中p110δ途徑對紅斑性狼瘡的治療是具有潛力的，若可以進一步研究p110δ在維持B-1細胞族群的重要性與相關機轉，也有助於闡明治療其他與B-1細胞相關之疾病，例如特定的黑色素瘤、淋巴瘤、及白血病等。 | zh_TW |
| dc.description.abstract | Systemic lupus erythematosus is an autoimmune disease caused by multiple pathogenic factors, such as genetic, hormone, environmental, and different abnormal immune components. Hyperreactivity of B cells, expecially B-1 cells, has been suggested to play a critical role in the development of autoantibodies. Previous studies have illustrated that depravation of B-1 cells was profitable to alleviate the disease aggravation. However, these approaches might result in subsequent unfavorable side-effects. P110δ, a leukocyte-specific catalytic subunit of PI3Ks, are proved to be able to abrogate the maturation of B cell lineages, especially the marginal zone B cell and B-1 cell populations. In this study, we plan to apply IC87114, a highly selective inhibitor of P110δ, to interfere the development of B-1 cells in murine NZB/W F1 model. Furthermore, we also studied the effect of IC87114 on B-1 cells both in vitro and in vivo. First, we found IC87114 could decrease the proliferation of splenocytes, B-1 and B-2 cells in dose-dependent response. The drug could also reduce IL-10 production of peritoneal resident cells and B-1 cells. Next, we treated Balb/c mice with IC87114 by peritoneal injection, the population and the activated level of B cells and T cells were not affected, but the proliferation of peritoneal washout cells were decreased. In murine lupus model, we treated NZB/W F1 mice with IC87114 since 2-months by peritoneal injection. Compared to the control group, we found the anti-ss/ds DNA IgG was decreased significantly in the low dose of IC87114 group. In summary, the P110δ inhibitor can suppress the proliferation and cytokine production of B cells effectively, but it did not affect the population, percentage and the activated manners of immune cells in vivo. In the lupus model, the auto-antibodies are decreased, supporting the notion that the p110δ inhibitor might be a potential therapeutic agent for SLE. Moreover, the evidence that PI3Ks are critical for the maintenance of B-1 cell populations might shed light on future exploring the potential treatment of other diseases associated with B-1 cells, such as certain melanoma, lymphoma, or leukemia. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-20T21:34:33Z (GMT). No. of bitstreams: 1 ntu-99-R97450001-1.pdf: 2165176 bytes, checksum: dbf957d078b9c14d457faef7e7b59edf (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 口試委員會審定書……………………………………………...………..……………..i
誌謝…………………………..………………………………………………………….ii 中文摘要.................................………………………………………………………….iii 英文摘要……………………………………….....................………………………….iv 目錄...................................................................................................................................1 圖目錄...............................................................................................................................3 縮寫表...............................................................................................................................5 第一章 研究背景…………….......................................................................................6 1.1 全身紅斑性狼瘡之背景介紹…………………...........…………………………….7 1.2 B-1細胞，IL-10與SLE的治療………………………………………….....……...9 1.3 PI3Ks，p110δ與B-1細胞……………........……………………………...……….11 1.4 PI3Ks抑制劑wortmannin與p110δ抑制劑 IC87114………………...…………..12 1.5 小干擾型核醣核酸與疾病治療之應用……………………………...……………13 1.6 SLE動物模式 NZB×NZW F1小鼠………………………………….……………14 1.7 研究目的……………………………………………………………………...……16 第二章 材料與方法…………….................................................................................17 2.1 實驗材料…………………………………….………………………………….....18 2.2 實驗方法…………………………………….………………………………….....22 2.3 數據統計與分析…………………………………………………………...……...31 第三章 實驗結果…………….....................................................................................32 3.1 p110δ抑制劑 IC87114 於ex vivo的實驗………..………………………………33 3.2 p110δ抑制劑 IC87114 於Balb/c小鼠之實驗結果………………………….......34 3.3 p110δ抑制劑 IC87114 於SLE動物模式NZB×NZW F1小鼠之實驗結果….....35 3.4 IL-10小干擾型核醣核酸的製備與效果評估………………….…..……………36 第四章 討論與結論……………….............................................................................38 圖表…………………………………………………………………………………….43 參考文獻……………………………………………………………………………….66 附錄…………………………………………………………………………………….75 | |
| dc.language.iso | zh-TW | |
| dc.title | 藉由抑制PI3K P110δ的活化途徑來研究對B-1細胞和狼瘡小鼠的影響 | zh_TW |
| dc.title | Targeting PI3K P110δ Pathway to Interfere B-1 Cells Functions and Decrease Activity of Murine Lupus | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 沈家瑞(Chia-Rui Shen),吳文勉(Wen-Mein Wu) | |
| dc.subject.keyword | 全身紅斑性狼瘡,PI3Ks,p110δ,B-1細胞,IL-10,NZB/W F1小鼠, | zh_TW |
| dc.subject.keyword | Systemic lupus erythematosus,PI3Ks,p110δ,B-1cells,IL-10,NZB/W F1, | en |
| dc.relation.page | 75 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2010-08-18 | |
| dc.contributor.author-college | 牙醫專業學院 | zh_TW |
| dc.contributor.author-dept | 口腔生物科學研究所 | zh_TW |
| Appears in Collections: | 口腔生物科學研究所 | |
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|---|---|---|---|
| ntu-99-1.pdf | 2.11 MB | Adobe PDF | View/Open |
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