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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許秉寧(Ping-Ning Hsu) | |
| dc.contributor.author | Shih-Duo Hsu Hung | en |
| dc.contributor.author | 徐洪世鐸 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:32:36Z | - |
| dc.date.available | 2021-08-30 | |
| dc.date.available | 2022-11-24T03:32:36Z | - |
| dc.date.copyright | 2021-08-30 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-10 | |
| dc.identifier.citation | Johnstone et al. (2002). Apoptosis: a linkbetween cancer geneticsand chemotherapy. Cell 108, 153-164. Wu, G.S. et al. (1999). Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor. Cancer Res. 59, 2770–2775. Falschlehner, C. et al. (2007). TRAIL signaling: decisions between life and death. Int. J. Biochem. Cell Biol. 39, 1462–1475. Wiley, S.R., et al. (1995). Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673-682. Hilliard B. et al. (2001). Roles of TNF-related apoptosis-inducing ligand in experimental autoimmune encephalomyelitis. J Immunol 166(2), 1314-9. Lehnert et al. (2014). TRAIL–Receptor Costimulation Inhibits Proximal TCR Signaling and Suppresses Human T Cell Activation and Proliferation. J Immunol 193, 4021-4031. Zhu, J., et al. (2014). TRAIL receptor deficiency sensitizes mice to dextran sodium sulphate-induced colitis and colitis-associated carcinogenesis. Immunology 141, 211-221. Chyuan, I.T. et al. (2017). An apoptosis-independent role of TRAIL in suppressing joint inflammation and inhibiting T-cell activation in inflammatory arthritis. Cellular molecular immunology. Cellular Molecular Immunology 14, 1–12. Chyuan, I.T. et al. (2018). Trail-Mediated suppression of T cell receptor signaling inhibits T cell activation and inflammation in experimental autoimmune encephalomyelitis. Front. Immunol. 9(15), 1-14. K.H. Mills, (2011). TLR-dependent T cell activation in autoimmunity. Nat. Rev. Immunol. 11, 807e822. I.I. Ivanov, et al. (2006). The orphan nuclear receptor RORgt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121e1133. X. Liu, et al. (2008). Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases. J. Immunol. 180, 6070e6076. Chi, H., (2012). Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338. Frauwirth, K.A. et al. (2002). The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777. Pearce, E.L. et al. (2013). Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454–1242454. Guma, M. et al. (2016). Metabolomics in rheumatic diseases: desperately seeking biomarkers. Nat. Rev. Rheumatol. 12, 269–281. Delgoffe, G.M. et al. (2011). The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303. Macintyre, A.N. et al. (2014). The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61–72. Shi, L.Z. et al. (2011). HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376. Zeng, H. et al. (2016). mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 45, 540–554. Zhou, L. et al. (2008). TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240. Gottschalk, R.A. et al. (2013). TCR ligand ensity and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 207, 1701–1711. Tubo, N.J. et al. (2013). Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153, 785–796. Klysz, D. et al. (2015). Glutamine-dependent α‑ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8, ra97. Guang L. Wang and Gregg L. Semenza. (1993). General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc. Natl. Acad. Sci. USA 90, 4304-4308. Kaelin, W.G. et al. (2008). Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402. Epstein, A.C. et al. (2001). C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54. Kim et al. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism 3, 177-185. Eric. V. Dang et al. (2011). Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1. Cell 146, 772-784. Hongbo Chi et.al. (2011). HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208(7), 1367-1376. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81140 | - |
| dc.description.abstract | 過去的研究已經發現Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)會引起多種腫瘤細胞株的細胞凋亡，以前也認為TRAIL是藉由促進免疫細胞的凋亡來抑制發炎反應。然而最近的研究已經證實TARIL抑制實驗性自體免疫腦脊髓炎(EAE)是藉由非細胞凋亡的途徑來抑制T細胞的免疫反應，但詳細的分子機制仍待研究。在EAE模式中，T helper 17 (Th17)細胞是主要引起中樞神經發炎的T細胞次群。又有研究指出Hypoxia-inducible factors (HIF-1α)的表現可促進Th17細胞的分化而降低調節性T細胞( Treg)的發育。過去我們實驗室的轉錄組分析也發現施打TRAIL的EAE小鼠，T細胞有較低的HIF-1α表現量，因此我們欲探討TRAIL是否藉由抑制HIF-1α的表現來調控Th17分化。 我們將小鼠脾臟中的CD4+ T細胞取出，在Th17分化環境下，於體外培養四天後再處理TRAIL 24小時，結果發現IL-17A的表現量下降的同時，也伴隨著Foxp3表現量上升，且RORγt的表現量也會受到TRAIL的抑制。我們也觀察到TRAIL無法抑制Treg細胞表現Foxp3，且TRAIL雖然會抑制Th1細胞表現IFN-γ卻無法促進Foxp3的表現。由此可知TRAIL對於Th17細胞的分化上扮演著重要的角色。此外，我們發現經過TRAIL處理的Th17細胞，HIF-1α無論是RNA或蛋白質的表現量都有顯著下降。而且藉由在細胞中過量表現HIF-1α會導致受到TRAIL抑制的Th17細胞之IL-17A表現量顯著回升。因此我們認為TRAIL抑制Th17細胞的分化是經由負向調控HIF-1α的表現量。先前的研究已經發現在EAE老鼠發病前施打TRAIL可以有效減緩其疾病的症狀，且在中樞神經系統中的IL-17A及IFN-γ也受到抑制。然而在本研究中觀察到發病後的老鼠再施打TRAIL後也可以使老鼠的疾病得到緩解，且脾臟中的CD4+ T細胞產生的IL-17A也顯著受到抑制。所以我們推測TRAIL可以抑制EAE老鼠體內已經分化的Th17細胞來減輕腦與脊髓的發炎程度。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:32:36Z (GMT). No. of bitstreams: 1 U0001-0908202110531800.pdf: 2634753 bytes, checksum: 1f0676c5b9f90eb73bf733c28af39051 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 誌謝……………………………………………………………………………………I 中文摘要…………………………………………………………………………….II Abstract……………………………………………………………………………...IV List of figures……………………………………………………………………...VIII Chapter 1 Introduction 1.1 Tumor necrosis factor-related apoptosis-inducing ligand…………………...1 1.2 TRAIL/TRAIL-R signal suppresses the activity of primary T cells………..2 1.3 Role of Th17 cells in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS)……………………………………………………3 1.4 Immune metabolism in T cells………………………………………………...5 1.5 Plasticity of Th17 cells…………………………………………………………6 1.6 Hypoxia inducing factor 1α (HIF-1α)………………………………………...7 1.7 Rationale………………………………………………………………………..9 Chapter 2 Material and Methods 2.1 Mice……………………………………………………………………………10 2.2 Enrichment of splenic CD4+ T cells………………………………………….10 2.3 T cell differentiation and suppression assay…………………………………11 2.4 Intracellular cytokine staining……………………………………………….12 2.5 Enzyme-Linked Immunosorbent Assay (ELISA)…………………………..12 2.6 Quantitative RT-PCR …………………………………………………….….12 2.7 Western Blot Analysis…………………………………………………….…..13 2.8 HIF-1α overexpression……………………………………………………….13 2.9 Purification of His-TRAIL……………………………………………….......14 2.10 Apoptosis assay……………………………………………………..………..15 2.11 Induction of EAE…………………………………………………………….15 2.12 Brain and spinal cord (CNS) lymphocytes isolation………………………16 2.13 Statistical analysis…………………………………………………………...16 2.14 Materials……………………………………………………………………..16 2.15 Primer………………………………………………………………………...18 Chapter 3 Results 3.1 TRAIL regulates the differentiation of polarized Th17 cells in vitro……..19 3.2 TRAIL inhibits the expression of HIF-1α in mRNA and protein level…….20 3.3 TRAIL decrease the severity of autoimmune encephalomyelitis while the disease is at the onset……………………………………………………………..21 3.4 TRAIL restore the cytokine production of Th17 cells………………………22 Chapter 4 Discussion……………………………………………………………….. 23 Reference……………………………………………………………………………. 36 | |
| dc.language.iso | en | |
| dc.subject | α | zh_TW |
| dc.subject | 腫瘤壞死因子相關凋亡誘導配體 | zh_TW |
| dc.subject | 實驗性自體免疫腦脊髓炎模式 | zh_TW |
| dc.subject | 第十七型輔助性T 細胞 | zh_TW |
| dc.subject | 缺氧誘導因子-1 | zh_TW |
| dc.subject | T helper 17 cells (Th17 cells) | en |
| dc.subject | Hypoxia-inducible factors (HIF-1α) | en |
| dc.subject | Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) | en |
| dc.subject | experimental autoimmune encephalomyelitis (EAE) model | en |
| dc.title | TRAIL藉由抑制HIF-1α調控Th17的分化 | zh_TW |
| dc.title | TRAIL Regulates Th17 Differentiation by Suppression of HIF-1α | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 全以祖(Hsin-Tsai Liu),司徒惠康(Chih-Yang Tseng),朱清良 | |
| dc.subject.keyword | 腫瘤壞死因子相關凋亡誘導配體,實驗性自體免疫腦脊髓炎模式,第十七型輔助性T 細胞,缺氧誘導因子-1,α, | zh_TW |
| dc.subject.keyword | Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL),experimental autoimmune encephalomyelitis (EAE) model,T helper 17 cells (Th17 cells),Hypoxia-inducible factors (HIF-1α), | en |
| dc.relation.page | 38 | |
| dc.identifier.doi | 10.6342/NTU202102198 | |
| 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 |
| 顯示於系所單位： | 免疫學研究所 | |
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