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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 李建國(Chien-Kuo Lee) | |
dc.contributor.author | Hsin-Wen Chang | en |
dc.contributor.author | 張馨文 | zh_TW |
dc.date.accessioned | 2021-06-08T04:18:55Z | - |
dc.date.copyright | 2010-09-09 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-07-26 | |
dc.identifier.citation | References
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22486 | - |
dc.description.abstract | B細胞發育始於骨髓中,而決定前趨細胞(precursors)是否能分化為B淋巴球主要是取決於轉錄因子(transcriptional factor)及細胞激素(cytokine)的調控。已知介白素-7(IL-7)和似Fms酪氨酸活化酶-3配合體(Flt3L)在早期B細胞發育過程扮演重要角色,第一型干擾素於近年也被發現可以影響造血幹細胞之增生。我們藉由研究第一型干擾素訊息傳導缺陷的STAT1基因剔除鼠來探討STAT1在B細胞發育中扮演的角色。我們的研究中發現,STAT1基因剔除小鼠的骨髓內,發育中各階段的B淋巴球所佔百分比及數量均有所下降。另外,在介白素-7的刺激下,缺乏STAT1的pro-B與pre-B細胞增生的反應也低於控制組之小鼠,其中原因之一是缺乏STAT1的小鼠骨髓中可對介白素-7有所反應之細胞數量低於控制組,而非因介白素-7受體表現量減少或其調控之訊息傳遞機制有缺陷。同時,我們也比較STAT1基因剔除鼠與另一種第一型干擾素訊息傳導有缺陷的STAT2基因突變鼠、及同時缺乏有功能之STAT1與STAT2的老鼠骨髓中B細胞的數量,發現只要老鼠骨髓中缺乏STAT1,B細胞數量即會下降,然而卻無關於STAT2功能的有無。接著藉由骨髓移植實驗,我們證實缺乏STAT1小鼠體內B細胞發育的缺陷,是由於骨髓細胞本身缺乏STAT1所造成。
令人驚訝的是,STAT1基因剔除鼠體內B細胞發育的缺陷在經過復育過程後,侷限至骨隨的pre-B及成熟B細胞兩個階段,且其骨髓中表現介白素-7受體的細胞亦恢復至與控制組無異。經由體外細胞培養實驗,我們發現表現介白素-7受體的細胞的增生反應在新復育之STAT1基因剔除鼠與控制組小鼠已無差異。類似現象亦發生於老鼠體內之骨髓增生實驗,由此可知STAT1可能並不影響介白素-7受體調控之訊息傳導。然而,藉由移植新復育之STAT1基因剔除鼠之骨髓,我們仍可觀察到週邊血中B細胞數量有所下降,表示骨髓中之B細胞發育需要STAT1存在。有趣的是,當把控制鼠之骨髓移植進STAT1基因剔除鼠體內,可觀察到其脾臟的B細胞仍有些微下降的現象,更暗示B細胞發育過程中周邊細胞也需有STAT1表現。 總歸而言,我們的研究指出STAT1可在早期B細胞發育過程中扮演一個正向調控角色,而且這個過程和介白素-7受體及STAT2的調控無關。此外,骨髓中細胞及非骨髓細胞中的STAT1在B細胞發育分別具有功能。 | zh_TW |
dc.description.abstract | Transcription factors and cytokine receptors are critical for instructing the development of B lymphocytes from progenitor cells in the bone marrow (BM). Cytokines such as IL-7 and Flt3L are involved in regulating early-stage of B lymphopoiesis. Type I interferons (IFNs) has also been shown to regulate the proliferation of hematopoietic stem cells (HSCs). Therefore, we investigate the role of STAT1, a crucial signal mediator of type I IFNs, in B cell development. Interestingly, mice lacking STAT1 displayed impaired B cell lymphopoiesis. Percentage of distinct stages of B cells, including pro-B, pre-B, and immature B cells were all found to be decreased in the absence of STAT1. Moreover, BM cells from STAT1KO (ST1KO) mice were hyporesponsive to IL-7, an essential cytokine for B lymphopoiesis. This defect was due to decreased number of IL-7-responsive cells rather than decreased expression of IL-7Rα or defective IL-7R signaling. Besides, the impaired development of B lymphocytes was not observed in a STAT2 hypomorphic mutant mouse that showed hyporesponsiveness to type I IFNs, suggesting that the defect seem in ST1KO mice may not due to the loss of IFN responses. A similar phenotype was observed in adoptive transfer of ST1KO BM cells into RAG1KO mice, suggesting that the impaired B lymphopoiesis in ST1KO mice is cell-autonomous.
Surprisingly, rederivation of the ST1KO mice, the impaired B-cell development was only limited to pre B and mature B subsets, and the percentage of IL-7Rα expressing cells became comparable with that of WT mice. In vitro proliferation of IL-7Rα-expressing B cells was comparable between newly derived ST1KO and WT mice. Besides, in vivo proliferation of different subsets of B cells in the BM also appeared to be normal, suggesting that STAT1 does not affect IL-7R-mediated signaling and that STAT1 does not influence cell proliferation in vivo. However, adoptive transfer of newly rederived ST1KO BM into RAGIKO mice still showed reduced number of B cells in the periphery, suggesting an intrinsic requirement of STAT1 for B cell development. Interestingly, slight decrease of B cells in the spleen was also observed in ST1KO female chimeric mice that had been adoptively transferred with WT BM cells, suggesting that there is an extrinsic requirement of STAT1 for B cell development. Taken together, we show that STAT1 plays a positive regulator in early-stage B cell development through an IL-7Rα-independent, STAT2-independent pathway, and functions both in a cell-autonomous and non-cell autonomous manner. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T04:18:55Z (GMT). No. of bitstreams: 1 ntu-99-R97449003-1.pdf: 1604859 bytes, checksum: ae8fc2e23edfb1b3abe2639ad6e62c35 (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | Abbreviations v
中文摘要 vii Abstract ix Chapter I Introduction 1 1.1 B cell Developmental Stages in Bone Marrow 1 1.2 Transcription Factors involved in B cell Commitment 2 1.3 Cytokines involved in B cell development 2 1.4 Type I interferon in B cell development 4 1.5 JAK-STATs signaling pathway 5 1.6 Physiological role of STAT1 7 1.7 Rationale and significances 8 Chapter II Materials and Methods 9 2.1 Mice 9 2.2 Antibodies and cytokines 9 2.3 Genotyping for targeted alleles 10 2.4 Flow cytometric analysis 10 2.5 Purification of B cells 11 2.6 BrdU proliferation assay in vitro and in vivo 12 2.7 Adoptive transfer 13 2.8 Statistical analysis 14 Chapter III Results 15 3.1 B cell development is impaired in the BM of ST1KO mice 15 3.2 Reduced responders and hypo-responsive to IL-7 in ST1KO mice from Level Biotechnology Incorporated 16 3.3 The dysfunction of B-cell development is mediated by STAT2-independent signaling pathway in ST1KO mice 20 3.4 Cell-autonomous requirement of STAT1 for normal B cell development 21 3.5 Different impair phenotype in B-cell development in ST1KO mice rederived in NLAC 23 3.6 Normal IL-7R-mediated signaling pathway in ST1KO mice 24 3.7 Comparable BrdU incorporation rate between WT and ST1KO mice in vivo 25 3.8 Cell-autonomous requirement of STAT1 and extrinsic flaws in ST1KO mice for normal B cell development 26 Chapter IV Discussions 28 4.1 Potential role of type I interferon in B cell development 28 4.2 Potential role of transcription factors involved in early B cell development through an IL-7Rα-independent pathway 29 4.3 Potential role of SCF and TSLP signaling pathway in B cell development 31 References 33 Figures 41 | |
dc.language.iso | en | |
dc.title | STAT1在B淋巴球發育過程中所扮演角色之研究 | zh_TW |
dc.title | Role of STAT1 in B Cell Development | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 嚴仲陽(Jeffrey J.-Y. Yen),呂春敏(Chuen-Miin Leu) | |
dc.subject.keyword | B淋巴球,發育, | zh_TW |
dc.subject.keyword | STAT1,B cell development, | en |
dc.relation.page | 72 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2010-07-26 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 免疫學研究所 | zh_TW |
顯示於系所單位: | 免疫學研究所 |
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