請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49352完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 朱清良 | |
| dc.contributor.author | Mu-Yun Lin | en |
| dc.contributor.author | 林牧昀 | zh_TW |
| dc.date.accessioned | 2021-06-15T11:24:53Z | - |
| dc.date.available | 2021-08-26 | |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-18 | |
| dc.identifier.citation | 1. Mocsai, A., J. Ruland, and V.L. Tybulewicz, The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol, 2010. 10(6): p. 387-402.
2. Rolli, V., et al., Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol Cell, 2002. 10(5): p. 1057-69. 3. Ying, H., et al., Syk mediates BCR- and CD40-signaling integration during B cell activation. Immunobiology, 2011. 216(5): p. 566-70. 4. Lowell, C.A., Src-family and Syk kinases in activating and inhibitory pathways in innate immune cells: signaling cross talk. Cold Spring Harb Perspect Biol,2011. 3(3). 5. Mocsai, A., et al., Syk is required for integrin signaling in neutrophils. Immunity, 2002. 16(4): p. 547-58. 6. Vines, C.M., et al., Inhibition of beta 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr. Immunity, 2001. 15(4): p. 507-19. 7. Sanderson, M.P., et al., Syk: a novel target for treatment of inflammation in lung disease. Inflamm Allergy Drug Targets, 2009. 8(2): p. 87-95. 8. Yanagi, S., et al., Syk expression and novel function in a wide variety of tissues. Biochem Biophys Res Commun, 2001. 288(3): p. 495-8. 9. Yanagi, S., et al., Syk expression in endothelial cells and their morphologic defects in embryonic Syk-deficient mice. Blood, 2001. 98(9): p. 2869-71. 10. Inatome, R., et al., A critical role for Syk in endothelial cell proliferation and migration. Biochem Biophys Res Commun, 2001. 286(1): p. 195-9. 11. Wang, H. and C.C. Malbon, G(s)alpha repression of adipogenesis via Syk. J Biol Chem, 1999. 274(45): p. 32159-66. 12. Hatterer, E., et al., Syk kinase is phosphorylated in specific areas of the developing nervous system. Neurosci Res, 2011. 70(2): p. 172-82. 13. Ruschel, A. and A. Ullrich, Protein tyrosine kinase Syk modulates EGFR signalling in human mammary epithelial cells. Cell Signal, 2004. 16(11): p.1249-61. 14. Ulanova, M., et al., Syk tyrosine kinase participates in beta1-integrin signaling and inflammatory responses in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol, 2005. 288(3): p. L497-507. 15. Van der Sluis, M., et al., Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology, 2006. 131(1): p. 117-29. 16. Velcich, A., et al., Colorectal cancer in mice genetically deficient in the mucin Muc2. Science, 2002. 295(5560): p. 1726-9. 17. Mukherjee, S. and L.V. Hooper, Antimicrobial defense of the intestine. Immunity, 2015. 42(1): p. 28-39. 18. Turner, J.R., Intestinal mucosal barrier function in health and disease. Nat Rev Immunol, 2009. 9(11): p. 799-809. 19. Saleh, M. and G. Trinchieri, Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat Rev Immunol, 2011. 11(1): p. 9-20. 20. Sturm, A. and A.U. Dignass, Epithelial restitution and wound healing in inflammatory bowel disease.World J Gastroenterol, 2008. 14(3): p. 348-53. 21. Sabat, R., W. Ouyang, and K. Wolk, Therapeutic opportunities of the IL-22-IL-22R1 system. Nat Rev Drug Discov, 2014. 13(1): p. 21-38. 22. Pickert, G., et al., STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med, 2009. 206(7): p. 1465-72. 23. Hainzl, E., et al., Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis. J Immunol, 2015. 195(10): p. 5011-24. 24. Mitra, A., S.K. Raychaudhuri, and S.P. Raychaudhuri, IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. Cytokine, 2012. 60(1): p. 38-42. 25. Lejeune, D., et al., Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J Biol Chem, 2002. 277(37): p. 33676-82. 26. Wolk, K., et al., IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol, 2006. 36(5): p. 1309-23. 27. Zheng, Y., et al., Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med, 2008. 14(3): p. 282-9. 28. Raffatellu, M., et al., Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med, 2008. 14(4): p. 421-8. 29. Pham, T.A., et al., Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe, 2014. 16(4): p. 504-16. 30. Schreiber, F., J.M. Arasteh, and T.D. Lawley, Pathogen Resistance Mediated by IL-22 Signaling at the Epithelial-Microbiota Interface. J Mol Biol, 2015. 427(23): p. 3676-82. 31. Zhou, Y.J., et al., Hierarchy of protein tyrosine kinases in interleukin-2 (IL-2) signaling: activation of syk depends on Jak3; however, neither Syk nor Lck is required for IL-2-mediated STAT activation. Mol Cell Biol, 2000. 20(12): p. 4371-80. 32. Tassiulas, I., et al., Amplification of IFN-alpha-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nat Immunol, 2004. 5(11): p. 1181-9. 33. Uckun, F.M., et al., STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress. Proc Natl Acad Sci U S A, 2010. 107(7): p. 2902-7. 34. Na, H.G., et al., Spleen tyrosine kinase induces MUC5AC expression in human airway epithelial cell. Am J Rhinol Allergy, 2016. 30(2): p. 89-93. 35. Lau, K.S., et al., BAY61-3606 affects the viability of colon cancer cells in a genotype-directed manner. PLoS One, 2012. 7(7): p. e41343. 36. Sauer, B., Inducible gene targeting in mice using the Cre/lox system. Methods, 1998. 14(4): p. 381-92. 37. Braselmann, S., et al., R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther, 2006. 319(3): p. 998-1008. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49352 | - |
| dc.description.abstract | 脾酪氨酸激酶(spleen tyrosine kinase, Syk)在免疫細胞裡的表現及功能在過去被廣泛研究，並發現它能參與許多免疫反應及細胞活化等的訊息傳遞。報導指出Syk 也存在於其他多種細胞內，但在腸道表皮細胞(intestinal epithelial cells)功能卻仍不清楚。腸道表皮細胞作為腸內菌及腸道免疫系統的屏障，對於腸道生理系統穩定的維持具有重要的作用，若功能缺失可能造成發炎性腸道疾病(inflammatory bowel disease, IBD)。為了研究Syk 在腸道表皮細胞的功能，我們生產出專一在腸道表皮細胞中缺乏Syk 的小鼠Sykflox/flox x Vil-cre，Syk△IEC)，然後發現在葡聚醣硫酸鈉(dextran sulfate sodium, DSS)引發腸炎的實驗模式中，此Syk 缺失的小鼠發炎情形會較野生型(WT)嚴重。接著我們想看Syk 的缺失是否會造成腸道表皮細胞容易進行細胞凋亡(apoptosis)，進一步導致更嚴重的腸炎。另外，我們想研究Syk 究竟參與哪一條訊息傳遞路徑，影響腸表皮細胞的功能。文獻指出介白素-22 (Interleukin-22, IL-22)可促進腸道細胞產生抗微生物肽(antimicrobial peptide, AMP)及黏膜蛋白(mucin)，減緩腸道發炎的情形；且報導指出IL-22 能藉由活化STAT3 及其他激酶，以調控細胞功能。此篇研究中，我們發現Syk 可能藉由參與IL-22-STAT3 的訊息傳遞，促進腸道表皮細胞產生抗微生物肽及黏膜蛋白，以維持腸道系統的恆定。 | zh_TW |
| dc.description.abstract | Spleen tyrosine kinase (Syk) is widely implicated in several immune responses and cell activation in various hematopoietic cells. While being detected in other tissues, the role and function of Syk in intestinal epithelial cells are still elusive. Intestinal epithelium functions as an essential barrier for maintenance of mucosal homeostasis, and its dysregulation causes the development of IBD. To study the function of Syk in intestinal epithelium, we generate mice with Syk-deficient intestinal epithelial cells (vil-cre x sykflox/flox, Syk△IEC), and then we demonstrate that the transgenic mice are more sensitive to DSS-induced colitis. Next, we examine whether Syk-deficiency contributes to the increased apoptosis of intestinal epithelial cells and thus to the exaggeration of experimental colitis. Moreover, we would like to investigate which signaling pathway Syk may be involved in and hence affect the function of intestinal epithelial cells. The interleukin 22 (IL-22) is known for ameliorating colitis through enhancing the production of intestinal antimicrobial peptides (AMPs) and mucin. The cytokine acts on its target cell via activating STAT3 and several other kinases. Here we found that Syk may play a positive role in IL-22-STAT3 pathway and also in the mucin and AMP production by intestinal epithelial cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T11:24:53Z (GMT). No. of bitstreams: 1 ntu-105-R03449011-1.pdf: 1391847 bytes, checksum: 10e023849eabb9665e63a1b1857533d8 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 誌謝…………………………………………………………………………………. ii
中文摘要……………………………………………………………………………. iii Abstract ..……………………………………………………………………………. iv Chapter 1 Introduction ...…………………………………………………………….. 1 1.1 Background………………………………………………………..….…….. 1 1.1.1 Spleen tyrosine kinase ……………………………………..……... 2 1.1.2 The role of Syk in non-hematopoietic tissues ……………….….... 3 1.1.3 Intestinal epithelium …………………………………………….... 3 1.1.4 Inflammatory bowel disease …………………………………….... 4 1.1.5 Intestinal IL-22-IL22R1 system …………………………………... 5 1.2 Rationale ………………………………………………………………….... 7 1.3 Specific aims ……………………………………………………………….. 8 Chapter 2 Materials and methods ……………………………………………. 10 2.1 Animals ……………………………………………………………………. 11 2.2 DSS-induced colitis ……………………………………………………….. 11 2.3 in vivo permeability assay ………………………………………………… 11 2.4 Cell culture and stimulation ………………………………………………. 12 2.5 Cell viability assay ………………………………………………………... 12 2.6 TER measurement ………………………………………………………… 12 2.7 ELISA ……………………………………………………………………... 13 2.8 Real-time PCR …………………………………………………………….. 13 2.9 Western blot analysis ……………………………………………………… 14 2.10 Statistic analysis …………………………………………………………. 14 Chapter 3 Results ………………………………………………………………….... 15 3.1 The role of Syk in IECs in vivo …………………………………………… 16 3.2 Syk had a minor role in maintaining the survival of IECs under DSS treatment in vitro ……………………………………………………………………. 16 3.3 Inhibition of Syk activity did not affect IEC monolayer permeability under DSS treatment in vitro ……………………………………………………. 17 3.4 STAT3 was less activated in the colons of Syk△IEC mice ………………….. 17 3.5 Syk inhibitor reduced the IL-22-STAT3 signaling pathway in IECs in vitro ……………………………………………………………………. 18 3.6 The role of Syk in the IL-22-mediated production of mucin, AMP and Fut2 by IECs in vivo ……………………………………………..………………... 19 3.7 Syk inhibitor decreased mucin, AMP and Fut2 expression in CMT-93 …… 19 Chapter 4 Discussion ………………………………………………………………... 21 4.1 The role of Syk in IECs during DSS-induced colitis in vivo ……………..... 22 4.2 Syk do not affect IEC survival which is decreased with DSS treatment in vitro ……………………..………………………………………………. 22 4.3 Syk do not affect the monolayer permeability of IECs under DSS treatment in vitro ……………………………………………………………………. 24 4.4 Syk plays a positive role in intestinal epithelial IL-22 signaling both in vitro and in vivo ………………………………………………………………... 24 4.5 The activation of Syk may be involved in the induction IL-22-dependent genes …………………………………………………………………...… 25 4.6 Conclusion ………………………………………………………………… 26 Chapter 5 Figures …………………………………………………………………… 27 Chapter 6 References ……………………………………………………………….. 38 | |
| dc.language.iso | en | |
| dc.subject | 黏膜蛋白 | zh_TW |
| dc.subject | 脾酪胺酸激? | zh_TW |
| dc.subject | 腸道表皮細胞 | zh_TW |
| dc.subject | 腸炎 | zh_TW |
| dc.subject | 介白素-22 | zh_TW |
| dc.subject | 抗微生物? | zh_TW |
| dc.subject | mucin | en |
| dc.subject | spleen tyrosine kinase (Syk) | en |
| dc.subject | intestinal epithelial cell | en |
| dc.subject | inflammatory bowel disease (IBD) | en |
| dc.subject | Interleukin 22 (IL-22) | en |
| dc.subject | antimicrobial peptide (AMP) | en |
| dc.title | Syk於腸道表皮細胞介白素-22訊息傳遞及維持腸道表皮完整性中扮演之角色 | zh_TW |
| dc.title | The role of Syk in intestinal epithelial IL-22 signaling pathway and in the gut integrity maintenance | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 廖南詩,余佳慧 | |
| dc.subject.keyword | 脾酪胺酸激?,腸道表皮細胞,腸炎,介白素-22,抗微生物?,黏膜蛋白, | zh_TW |
| dc.subject.keyword | spleen tyrosine kinase (Syk),intestinal epithelial cell,inflammatory bowel disease (IBD),Interleukin 22 (IL-22),antimicrobial peptide (AMP),mucin, | en |
| dc.relation.page | 46 | |
| dc.identifier.doi | 10.6342/NTU201602751 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-08-18 | |
| 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 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-105-1.pdf 未授權公開取用 | 1.36 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。