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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許秉寧 | |
| dc.contributor.author | Wei-Cheng Lin | en |
| dc.contributor.author | 林威成 | zh_TW |
| dc.date.accessioned | 2021-06-15T06:55:20Z | - |
| dc.date.available | 2016-03-03 | |
| dc.date.copyright | 2011-03-03 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-02-10 | |
| dc.identifier.citation | Akopyants, N.S., Clifton, S.W., Kersulyte, D., Crabtree, J.E., Youree, B.E., Reece, C.A., Bukanov, N.O., Drazek, E.S., Roe, B.A., and Berg, D.E. (1998). Analyses of the cag pathogenicity island of Helicobacter pylori. Mol Microbiol 28, 37-53.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48400 | - |
| dc.description.abstract | 胃幽門螺旋桿菌的感染與慢性胃炎和消化性潰瘍甚至是胃癌和胃粘膜相關淋巴組織淋巴瘤的疾病發生有關。胃幽門螺旋桿菌引發胃部疾病的致病性機轉主要可分成兩個部份來探討：一部分是胃幽門螺旋桿菌本身所具有的毒性因子所造成的毒殺作用，另一部份則是引發宿主產生的發炎反應所造成的影響。胃幽門螺旋桿菌造成疾病發生的角色已被證實，但引發致病性的相關機轉仍不清楚。
首先，為了探討胃幽門螺旋桿菌對於腫瘤發生的相關機轉，我們探討胃幽門螺旋桿菌CagA蛋白對於粘膜相關淋巴組織淋巴瘤發生機轉所扮演的角色。先前的研究報告指出胃幽門螺旋桿菌可以藉由依附胃上皮細胞將CagA蛋白送入細胞中，被送入細胞內的CagA蛋白可以調節細胞內的訊息傳導路徑並且引發致病性，因此我們認為在胃幽門螺旋桿菌感染的過程中，可能藉由與B細胞的直接作用來造成粘膜相關淋巴組織淋巴瘤。我們證實胃幽門螺旋桿菌可以將CagA蛋白送入人類B細胞中，並且在細胞內進行酪氨酸的磷酸化作用後，與細胞內的SHP-2進行結合，另外，CagA蛋白還會活化細胞內的ERK與p38 MAP kinase，並且造成細胞內存活相關因子Bcl-2和Bcl-XL的表現量增加，進一步防止細胞死亡。本研究顯示胃幽門螺旋桿菌可以直接將CagA致癌蛋白送入人類的B細胞中，造成粘膜相關淋巴組織淋巴瘤及病的發生。 第二，為了探討宿主因子在胃幽門螺旋桿菌引發疾病的過程中所扮演的角色，於是我們研究胃幽門螺旋桿菌所引起細胞凋亡的現象之中TRAIL分子扮演的角色。在我們先前的研究指出，胃幽門螺旋桿菌可以改變胃上皮細胞對於TRAIL的感受性改變，使細胞進行細胞凋亡，我們進一步研究指出胃幽門螺旋桿菌可引發TRAIL所造成細胞內caspase-8、casapse-3以及mitochondria的活化，因而誘發胃上皮細胞的細胞凋亡作用，同時也發現，胃幽門螺旋桿菌可加強TRAIL所引發death inducing signaling complex (DISC) 的聚集，因此引發足夠多的caspase-8活化，因而打破原本的抗性，造成細胞的敏感性增加，此過程是經由胃幽門螺旋桿菌誘發c-FLIPS的表現量降低所造成，此外，在細胞內過度表現c-FLIPS可以阻斷TRAIL所引起的細胞凋亡，進一步單獨利用c-FLIPS siRNA就可以改變細胞對於TRAIL的感受性，證實其重要性。因此，胃幽門螺旋桿菌可以經由降低細胞內c-FLIPS的表現，因而加強細胞內DISC的聚集，藉此活化較多caspase-8，因而調控胃上皮細胞對於TRAIL的感受性。 總結，致病菌因子與宿主因子在胃幽門螺旋桿菌所導致的疾病發展過程中扮演重要的角色，對於胃幽門螺旋桿菌引發疾病的過程中是很重要的致病機轉。 | zh_TW |
| dc.description.abstract | Infection with the gastric pathogen H. pylori infection has been associated with the development of chronic gastritis and peptic ulcer diseases, moreover, gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori infection leads to pathogenesis of gastric diseases mainly by two different mechanisms : direct toxicity of H. pylori virulent factors and induction of inflammatory responses. The role of H. pylori in association with disease development has been demonstrated, however, the mechanisms underlying pathogenesis are still unclear.
First, in order to investigate the mechanisms underlying H. pylori induces the tumourgenesis, we examine the role of H. pylori CagA in the development of MALT lymphoma. Previous studies reveal that H. pylori attaches to the epithelial cells, and translocates CagA proteins into cells. Intracellular CagA deregulates intracellular sighaling pathway and causes the pathogenic effects. This in turn raised the possibility that H. pylori is associated with the development of MALT lymphomas during persistent infection by direct interaction with B lymphocytes. We demonstrated that H. pylori directly translocates CagA into human B cell line and primary B cells. Furthermore, injected CagA undergoes tyrosine phosphorylation and interacts with SHP-2. Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase were activated upon CagA translocation. The cell survival factors, such as Bcl-2 and Bcl-XL were upregulated through the translocated CagA, moreover, prevents apoptosis. These results provide evidence that CagA is directly delivered into B cells by H. pylori and acts as a bacterium-derived oncoprotein in human B cells to cause the development of MALT lymphoma. Second, to study the role of host factors in regulating H. pylori-induced gastric diseases, we investigated the role of TNF related-apoptosis inducing ligand (TRAIL) in the induction of apoptosis during H. pylori infection. In our previous study, we provided the evidences that H. pylori can sensitize human gastric epithelial cells to TRAIL-mediated apoptosis. Further, we demonstrated that H. pylori could sensitize gastric epithelial cells to TRAIL, resulting in caspase-8, caspase-3 and mitochondrial pathway activation and induce apoptosis. H. pylori could enhance the death inducing signaling complex (DISC) assembly and induce sufficient amount of caspase-8 activation to break apoptosis resistance, inducing the TRAIL sensitivity via downregulation of the c-FLIPS in gastric epithelial cells. Overexpression of c-FLIPS could block apoptosis induced by TRAIL in the presence of H. pylori. Moreover, silencing c-FLIPS expression by siRNA increased TRAIL-induced apoptosis in human gastric epithelial cells. In summary, our data suggest that H. pylori could downregulate the expression level of c-FLIPS, resulting in enhanced DISC assembly and caspase-8 activation to modulate TRAIL-mediated apoptosis in gastric epithelial cells. Taken together, pathogen and host factors are critical in the development of H. pylori-associated diseases, the interplay between H. pylori and immune cells as well as gastric epithelial cells play important roles in the pathogenesis of H. pylori-mediated gastric disease. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T06:55:20Z (GMT). No. of bitstreams: 1 ntu-100-D92449003-1.pdf: 3124331 bytes, checksum: fe5fe6856cbd729eb88d55d6ab18aa9e (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | CHAPTERⅠ Introduction 1
Background 2 1. Helicobacter pylori 2 2. H. pylori pathogenesis 2 3. H. pylori CagA and Cancer 4 4. H. pylori and gastric MALT lymphoma 5 5. H. pylori and apoptosis 5 6. TRAIL and TRAIL receptors 6 7. TRAIL-induced signaling 7 8. Regulation of TRAIL induced apoptosis 8 9. c-FLIP 11 Aims of this study 11 The role CagA in the development of gastric MALT lymphoma 11 The molecular mechanisms of TRAIL-induced apoptosis during H. pylori infection 12 CHAPTERⅡ Materials and methods 14 Materials 15 1. Cells 15 2. Bacteria 15 3. Antibodies 16 4. Chemicals and reagents 18 5. Medium and Buffer 20 6. General materials 22 Methods 23 1. Expression and purification of recombinant TRAIL protein 24 Purification of His-TRAIL protein 24 Examine the function of His-TRAIL by PI staining 25 2. Cell apoptosis assay 25 Cell death detection ELISA 25 3. Cell viability assay 26 MTT assay 26 4. DISC analysis 26 5. Western blot 26 6. Preparation of the cytosolic fraction for the analysis of cytochrome c release 27 7. Isolation of human B lymphocytes 27 Purification of PBMC by Ficoll-Paque PLUS density preparation 27 Isolation of human B cells by PE-labeled cell selection cocktail 28 8. Cell surface staining 28 9. Establishment of H. pylori mutants 29 Constructions of cagA and cagE mutants 29 Construction of CagA-EGFP H. pylori 29 10. Cellular fractionation 31 11. Laser scanning confocal immunofluorescence microscopy 31 12. H. pylori culture 31 13. Immunoprecipitation and co-immunoprecipitation 32 14. RNAi knockdown assay 32 CHAPTERⅣ Results 33 PartⅠ The role of CagA in the development of gastric MALT lymphoma 34 1. H. pylori could directly translocate CagA into the human B cell line BJAB. 34 2. H. pylori could translocate CagA into B cells through type IV secretion system 35 3. CagA translocation induces activation of mitigen-activated protein kinase and upregulation of the anti-apoptotic proteins, Bcl-2 and Bcl-XL, in human B lymphocytes 36 4. Direct translocation of the CagA protein into primary human B lymphocytes after infection with H. pylori 37 PartⅡ The molecular mechanisms of TRAIL-induced apoptosis during H. pylori infection 37 1. H. pylori sensitizes gastric epithelial cells to TRAIL-induced apoptosis 37 2. H. pylori induces TRAIL sensitivity is dependent on caspase activation 38 3. H. pylori regulates TRAIL apoptotic signal via the mitochondrial type Ⅱ pathway 39 4. H. pylori enhances TRAIL-induced death inducing signaling complex 39 5. H. pylori regulates TRAIL-induced apoptosis by downregulating FLIPS expression 40 CHAPTERⅤ Discussions 42 1. H. pylori directly translocates CagA oncoprotein into human B cells 43 2. CagA provides oncogenic potential for the development of MALT lymphoma 43 3. Synergistic effect of CagA in the regulation of B cells activation 45 4. H. pylori regulates TRAIL sensitivity by affecting intracellular caspase signaling pathway, rather than upregulating the surface expression of death receptors 45 5. H. pylori modulates TRAIL-induced apoptosis through mitochondrial signaling pathway 47 6. H. pylori enhances TRAIL-induced DISC assembly 48 7. Downregulation of c-FLIPS is critical for H. pylori-induced TRAIL sensitivity 48 8. Conclusions 49 References 50 Figures 64 Appendix 93 | |
| dc.language.iso | en | |
| dc.subject | 胃上皮細胞 | zh_TW |
| dc.subject | 胃幽門螺旋桿菌 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | 胃粘膜相關淋巴組織淋巴瘤 | zh_TW |
| dc.subject | B cells | en |
| dc.subject | H. pylori | en |
| dc.subject | apoptosis | en |
| dc.subject | gastric mucosa-associated lymphoid tissue (MALT) lymphoma | en |
| dc.subject | TRAIL | en |
| dc.subject | gastric epithelial cells | en |
| dc.title | 胃幽門螺旋桿菌在調控細胞活化與凋亡之研究 | zh_TW |
| dc.title | Regulation of host cells activation and apoptosis by H. pylori | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 王錦堂,謝世良,司徒惠康,嚴仲陽 | |
| dc.subject.keyword | 胃幽門螺旋桿菌,細胞凋亡,胃粘膜相關淋巴組織淋巴瘤,胃上皮細胞, | zh_TW |
| dc.subject.keyword | H. pylori,apoptosis,gastric mucosa-associated lymphoid tissue (MALT) lymphoma,TRAIL,gastric epithelial cells,B cells, | en |
| dc.relation.page | 95 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-02-10 | |
| 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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