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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 許秉寧(Pin-Ning Hsu) | |
| dc.contributor.author | Szu-Chieh Wang | en |
| dc.contributor.author | 王思傑 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:32:55Z | - |
| dc.date.available | 2021-08-18 | |
| dc.date.available | 2022-11-24T03:32:55Z | - |
| dc.date.copyright | 2021-08-18 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-09 | |
| dc.identifier.citation | Balagopalan, L., Kortum, R.L., Coussens, N.P., Barr, V.A., and Samelson, L.E. (2015). The Linker for Activation of T Cells (LAT) Signaling Hub: From Signaling Complexes to Microclusters. J Biol Chem 290, 26422-26429. Barreto, M., Ferreira, R.C., Lourenco, L., Moraes-Fontes, M.F., Santos, E., Alves, M., Carvalho, C., Martins, B., Andreia, R., Viana, J.F., et al. (2009). Low frequency of CD4(+)CD25(+) Treg in SLE patients: a heritable trait associated with CTLA4 and TGF gene variants. BMC Immunol 10, 14. Bonelli, M., Smolen, J.S., and Scheinecker, C. (2010). Treg and lupus. Ann Rheum Dis 69, 65-66. Chiang, G.G., and Sefton, B.M. (2001). Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. J Biol Chem 276, 23173-23178. Cho, S.H., Raybuck, A.L., Blagih, J., Kemboi, E., Haase, V.H., Jones, R.G., and Boothby, M.R. (2019). 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J Autoimmun 33, 270-274. Zhao, X.F., Pan, H.F., Yuan, H., Zhang, W.H., Li, X.P., Wang, G.H., Wu, G.C., Su, H., Pan, F.M., Li, W.X., et al. (2010). Increased serum interleukin 17 in patients with systemic lupus erythematosus. Mol Biol Rep 37, 81-85. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81146 | - |
| dc.description.abstract | "腫瘤壞死因子相關凋亡誘導配體在過往的認知中主要是被認為可以引起細胞凋亡，然而在我們實驗室過去所做的研究中證明TRAIL在許多小鼠自體免疫疾病模型中可以透過非自然凋亡的途徑來大幅減少疾病活性和發炎，並且是藉由抑制T細胞啟動以及活性所導致。在研究中指出TRAIL以及TRAIL受體的交互作用可以抑制T細胞受體訊息傳遞相關分子磷酸化，並且防止這些分子進入脂筏當中來抑制T細胞活化。 在我的研究中發現TRAIL除了可以抑制ZAP70等訊息傳遞分子磷酸化之外，還可以抑制更上游分子包括Lck,CD3ζ磷酸化。因此我們進一步利用免疫沉澱法發現TRAIL受體和SHP-1之間有所交互作用，並且在TRAIL刺激下能促使SHP-1鄰酸化，而在TRAIL-R去除的小鼠當中也可觀察到磷酸化的SHP-1明顯減少的現象，因此推測TRAIL可能是透過SHP-1來抑制整個T細胞受體訊息傳遞相關分子的磷酸化。為了證明這件事，我們利用了過氧酸鹽以及SHP-1 siRNA的實驗來驗證TRAIL所引發的抑制效果的確是透過SHP-1這種磷酸酶，結果證實在TRAIL和過氧酸鹽共同刺激下或是在SHP-1 siRNA的處理下的確能夠有效地抑制TRAIL 所引發的抑制效果，因此，藉由這些實驗我們證實了TRAIL確實是透過SHP-1來抑制整個T細胞受體訊息傳遞分子磷酸化的過程。 此外，在我們實驗室之前轉錄體分析(transcriptome analysis)發現TRAIL除了直接抑制T細胞受體(TCR)訊息傳導之外，也可以藉由抑制T細胞免疫代謝的方式來調控T細胞的功能。因此我們挑選了全身性紅斑狼瘡(SLE)作為我們主要的研究對象。SLE是一種全身性多器官的自體免疫疾病，致病機轉主要是由於患者體內產生出自體抗體以及具有自我反應性的T細胞。其中，T細胞是導致SLE疾病中組織炎症的主因，並且也有研究指出免疫細胞代謝能力和其細胞的功能有直接的關聯性，在先前的研究指出在腎小管浸潤T細胞中會高量表現HIF-1α，並且HIF-1α的表現量會直接影響到T細胞糖解作用的效率以及T細胞的活性。 我第二部分的實驗可以分為幾個點進行探討。第一，TRAIL在SLE患者中的表現量高低以及和HIF-1α表現量之間的關聯性。第二，可溶性TRAIL和SLE病人的臨床病徵、活性變化的關聯性。第三，在體外試驗的情況下觀察TRAIL是否能抑制SLE病人T細胞分泌細胞激素的能力，作為未來臨床治療SLE的潛在藥物之一。首先，我們先利用大數據GEO分析SLE病人以及健康人T細胞內TRAIL,TRAIL受體,HIF-1α和GLU1以及RORC的基因表現量，數據顯示TRAIL和TRAIL受體在SLE病人的輔助型T細胞內基因表現量較低而其他代謝相關基因表現量則是較高，接著我們分析實際收到的病人中相關基因以及蛋白質表現量， 結果顯示無論在基因或是蛋白質表現上皆與GEO數據一致，TRAIL和TRAIL受體在SLE病人的輔助型T細胞內表現量較低而其他代謝相關蛋白質表現量則是較高。接著我們進一步分析病人血漿中可溶性TRAIL和臨床表徵的關聯性，我們發現可溶性TRAIL在SLE病人中表現量較低，其中在疾病活性較高的病人中又比活性低的病人來的更低，並且TRAIL和其他臨床表徵中如P/C ratio及全身性紅斑性狼瘡疾病活動性指數等具有顯著的負相關。再者，我們藉由CD3/28刺激3天後分析SLE病人輔助型T細胞的反應性，發現無論是TRAIL,TRAIL受體,以及其他代謝相關基因都有顯著上升的趨勢，表示SLE的輔助型T細胞具有較強的反應性。最後，我們在體外將TRAIL和SLE病人輔助型T細胞共同培養，發現TRAIL可以有效的降低SLE病人輔助型T細胞代謝相關蛋白質的表現，並且能有效地抑制介白素-17和干擾素γ蛋白質表現。總結而言，TRAIL在SLE病人中表現量較低並且其表現量和許多臨床表徵具有負向相關，同時TRAIL能夠有效抑制SLE病人促發炎細胞素的產生，因此在未來的確具有作為治療SLE疾病藥物的潛力。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:32:55Z (GMT). No. of bitstreams: 1 U0001-0808202113490400.pdf: 3253903 bytes, checksum: 64f756cc619c06738c9629c54e9fae04 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "致謝 i 中文摘要 ii Abstract iv Contents vii List of Figures x Chapter 1 Introduction 1 1. TRAIL 1 1.1 TRAIL and its receptors 1 1.2 TRAIL and apoptosis 2 1.3 TRAIL and apoptosis independent pathway 3 2. TCR signaling in T cell activation 4 2.1 TCR signaling response 4 2.2 Regulation of Lck tyrosine kinase 5 2.3 Regulation of ZAP-70 tyrosine kinase 5 3. Systemic lupus erythematosus (SLE) 6 4. T cell and B cell in SLE pathogenesis 7 4.1 T cell 7 4.1.1 Th1 in SLE 7 4.1.2 Th2 in SLE 8 4.1.3 Th17 in SLE 9 4.1.4 Treg in SLE 10 4.2 B cell 10 5. T cell metabolism in SLE patient 11 Chapter 2 Materials and Methods: 14 1. Materials 14 1.1 Primer 14 1.2 Antibodies 15 1.3 Kits 17 1.4 Transfection Reagent 18 1.5 Chemicals and reagents 18 1.6 Buffer 19 1.7 Recombinant protein 21 Methods 22 2.1 Western blot 22 2.2 Co-immunoprecipitation (Co-IP) 22 2.3 siRNA transfection 23 2.4 Subject 23 2.5 Isolation of human and mouse T cells 24 2.6 Human and mouse T cell culture 24 2.7 Enzyme-linked immunosorbent assay 25 2.8 Quantitative PCR analysis 25 2.9 Analysis cell death by flow cytometry 26 2.10 Carboxyfluorescein succinimidyle ester (CFSE) staining 26 2.11 Surface marker staining 27 2.12 Intracellular staining 27 2.13 Gene Expression Omnibus (GEO) data analysis 28 2.14 Statistical analysis 28 Chapter 3 Results 29 1. TRAIL suppressed T cell activity by inhibit TCR signaling molecules phosphorylation in an apoptosis-independent manner. 29 2. TRAIL-R was associated with SHP-1 and TRAIL alone stimulation could induce phosphorylated SHP-1 expression. 30 3. TRAIL/TRAIL-R interaction could promote phosphorylated SHP-1 expression in WT mice and this phenomenon was abolished in TRAIL-R KO mice. 30 4. Pervanadate treatment can reverse the inhibition effect of TRAIL in TCR signaling in EL4 cells 31 5. siRNA knock down SHP-1 reversed the inhibition effect of TRAIL in TCR signaling 32 6. GEO database analyzed gene expression between SLE patient and healthy individual 32 7. TRAIL and DR5 were downregulated and GLU-1, HIF-1α were upregulated in mRNA and protein expression in HC and SLE CD4+ T cells 33 8. The correlation between TRAIL and clinical manifestations of SLE 34 9. The responsiveness of CD4+ T cell were higher in SLE patient compared to healthy individual after CD3/28 stimulation for 3 days 35 10. TRAIL treatment normalized HIF-1α, GLU1, RORγt and pro-inflammatory cytokine IL-17 and IFN-γ production ability in SLE patient. 36 Chapter 4 Discussion 37 1. The mechanism of TRAIL/TRAIL-R inhibited T cell activation and metabolism 37 2. Whether the location of TRAIL-R was close enough to affect TCR synapse. 37 3. Whether there were functional differences between TRAIL induced phosphorylated SHP-1 and CD3/28 signaling induced phosphorylated SHP-1. 38 4. The concerns of TRAIL for clinical therapy 38 5. The difference between previous report of the amount of TRAIL in SLE patients. 40 Chapter 5 Figure 42 Chapter 6 References 67" | |
| dc.language.iso | en | |
| dc.subject | 腫瘤壞死因子相關凋亡誘導配體(TRAIL) | zh_TW |
| dc.subject | T細胞活化 | zh_TW |
| dc.subject | T細胞受體訊息傳遞分子 | zh_TW |
| dc.subject | 磷酸酶 | zh_TW |
| dc.subject | 全身性紅斑狼瘡(SLE) | zh_TW |
| dc.subject | Th17及IL17 | zh_TW |
| dc.subject | 免疫細胞代謝 | zh_TW |
| dc.subject | 缺氧誘導因子1α(HIF-1α) | zh_TW |
| dc.subject | immune metabolism | en |
| dc.subject | TNF-related apoptosis-inducing ligand (TRAIL) | en |
| dc.subject | Hypoxia induce factor1α(HIF-1α) | en |
| dc.subject | TCR signaling | en |
| dc.subject | SHP-1 | en |
| dc.subject | Systemic lupus erythematosus (SLE) | en |
| dc.subject | Th17 and Interleukin17 | en |
| dc.title | TRAIL透過SHP-1抑制近端TCR訊息傳遞分子磷酸化來調控T細胞活化 | zh_TW |
| dc.title | TRAIL inhibits T cell activation by suppressing phosphorylation of proximal TCR signaling through SHP-1 | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 朱清良(Hsin-Tsai Liu),楊皇煜(Chih-Yang Tseng),吳建陞 | |
| dc.subject.keyword | T細胞活化,T細胞受體訊息傳遞分子,磷酸酶,全身性紅斑狼瘡(SLE),Th17及IL17,免疫細胞代謝,缺氧誘導因子1α(HIF-1α),腫瘤壞死因子相關凋亡誘導配體(TRAIL), | zh_TW |
| dc.subject.keyword | TCR signaling,SHP-1,Systemic lupus erythematosus (SLE),Th17 and Interleukin17,immune metabolism,Hypoxia induce factor1α(HIF-1α),TNF-related apoptosis-inducing ligand (TRAIL), | en |
| dc.relation.page | 78 | |
| dc.identifier.doi | 10.6342/NTU202102185 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-08-10 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 免疫學研究所 | zh_TW |
| Appears in Collections: | 免疫學研究所 | |
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|---|---|---|---|
| U0001-0808202113490400.pdf Access limited in NTU ip range | 3.18 MB | Adobe PDF |
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