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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 江皓森(Hao-Sen Chiang) | |
| dc.contributor.author | Chen-Min Weng | en |
| dc.contributor.author | 翁甄敏 | zh_TW |
| dc.date.accessioned | 2021-06-17T01:53:27Z | - |
| dc.date.available | 2027-12-31 | |
| dc.date.copyright | 2017-07-28 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-07-24 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67846 | - |
| dc.description.abstract | 白色念珠菌(Candida albicans)是人類常見的共生真菌，然而當免疫能力失調時，它也會轉變成伺機型病原菌導致疾病。嗜中性白血球(Neutrophils)是在哺乳類體內中數量最多的白血球，且在對抗真菌的免疫反應扮演非常重要的角色。近期研究發現嗜中性白血球有個特殊的殺菌機制，會將細胞核的染色體結構解旋後釋放出去，稱為嗜中性胞外網狀結構（Neutrophil Extracellular Traps, NETs），這種網狀結構會纏繞病原菌，使其無法擴散，然後促進其清除和分解。由於微小管(Microtubules)和肌動蛋白(Actins)會調控NETs的形成，且Guanine nucleotide exchange factor H1 (GEF-H1)可以藉由調節RhoA GTPases的活性，進而影響下游微小管和肌動蛋白的動態平衡，因此本論文欲探討GEF-H1在NETs形成時所扮演的角色。藉由使用缺乏GEF-H1的基因改造小鼠，發現GEF-H1並不會影響嗜中性白血球在骨髓中的生成，也不會改變嗜中性白血球內的微小管與肌動蛋白的結構。利用Phorbol 12-myristate 13-acetate (PMA)刺激嗜中性白血球讓其產生NETs，發現在GEF-H1缺陷的小鼠嗜中性白血球的活性氧化物質(Reactive oxygen species, ROS)形成量不受影響，但Neutrophil elastase (NE)、Myeloperoxidase (MPO)和瓜氨酸化組蛋白H3 (Citrullinated histone H3, citH3)在細胞核內的表現量卻減少，且進而影響到NETs形成明顯下降的現象。當將菌絲狀(hyphae)的白色念珠菌與嗜中性白血球一同培養時，和正常的嗜中性白血球相比，缺少GEF-H1的嗜中性白血球形成較少的NETs。綜合以上實驗結果，可推論GEF-H1會調控NETs形成。 | zh_TW |
| dc.description.abstract | Candida albicans is common commensal fungi in human. However, they can also cause fetal disease in immunocompromised patients. Neutrophils are the most abundant type of white blood cells in most mammals, and play a critical role in defense of fungal infection. Previous studies have shown that neutrophils trap and kill a variety of pathogens by neutrophil extracellular traps (NETs), whose formation depends on histone citrullination and dynamic microtubule networks. The guanine nucleotide exchange factor H1 (GEF-H1) is crucial in coupling microtubule dynamics to RhoA GTPase activation in a variety of normal biological situations. It is also a newly defined component of cellular defenses for the detection of microbial effectors during cell invasion by pathogens. However, it remains unknown whether GEF-H1 regulates NET formation in response to pathogen infection. Here I show that GEF-H1 did not affect granulopoiesis of neutrophils in the bone marrow. The actin and microtubule networks were comparable between mouse naïve wild-type and GEF-H1-deficient neutrophils. In naive state, the level of citrullinated histone 3 was reduced in GEF-H1–deficient neutrophils. After activation by phorbol 12-myristate 13-acetate (PMA), the rate of NET release was reduced in GEF-H1–deficient neutrophils compared to wild-type neutrophils. The reduced NET formation in GEF-H1-deificient neutrophils was not to due to the impaired reactive oxygen species (ROS) production. The decreased translocation of neutrophil elastase (NE) and myeloperoxidase (MPO) into nucleus and histone H3 citrulination was observed in GEF-H1-deficient neutrophils. I further found that GEF-H1 deficiency lead to impaired NET formation, ROS production and antifungal immunity in response to Candida albicans infection. Overall, our results suggested a potential role for GEF-H1 in the regulation of NET formation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T01:53:27Z (GMT). No. of bitstreams: 1 ntu-106-R04b21005-1.pdf: 5467541 bytes, checksum: 0257c8b9225ba465abff78492032398c (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
致謝 ii 中文摘要 iii ABSTRACT v Contents vii List of figures x Chapter 1 Introduction 1 1.1 Candida albicans 1 1.2 Neutrophils 2 1.2.1 Granulopoiesis and innate immune response 2 1.2.2 Neutrophil extracellular traps 3 1.3 GEF-H1 6 1.3.1 Cell cytoskeleton 6 1.3.2 Function of GEF-H1 6 1.3.3 The function of GEF-H1 in immunity 7 1.4 Specific aim 8 Chapter 2 Materials and Methods 10 2.1 Mice 10 2.2 Genotyping of the Arhgef2+/+, Arhgef2+/−, and Arhgef2−/− mice 10 2.3 Isolation of murine neutrophils from bone marrow 11 2.4 Flow cytometry 12 2.5 Fungal culture and hyphal filamentation 13 2.6 Quantification of NET formation 13 2.7 Immunofluorescence Visualization of NETs 14 2.8 Immunoblotting 15 Chapter 3 Results 17 3.1 Comparable amounts of neutrophils are detected in the bone marrow of WT and Arhgef2-/- mice 17 3.2 NET formation in response to PMA activation is impaired in GEF-H1-deficient neutrophils 18 3.3 Chromatin decondensation and histone citrullination induced by PMA stimulation are impaired in GEF-H1-deficient neutrophils 20 3.4 NET formation in response to Candida albicans infection is impaired in GEF-H1-deficient neutrophils 21 3.5 ROS production in response to Candida albicans infection are impaired in GEF-H1-deficient neutrophils 23 Chapter 4 Discussion 25 Chapter 5 Conclusion 31 Reference 32 Figures 44 Tables 59 Appendix 61 | |
| dc.language.iso | en | |
| dc.title | GEF-H1調控嗜中性白血球胞外網狀結構的形成 | zh_TW |
| dc.title | The impact of GEF-H1 on neutrophil extracellular traps formation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 賈景山(Jean-San Chia),陳俊任(Chun-Jen Chen),鍾筱菁(Chiau-Jing Jung) | |
| dc.subject.keyword | 白色念珠菌,嗜中性白血球,嗜中性胞外網狀結構,GEF-H1,活性氧化物質,瓜氨酸化組蛋白H3, | zh_TW |
| dc.subject.keyword | Candida albicans,Neutrophils,Neutrophil extracellular traps,GEF-H1,Reactive oxygen species,Citrullinated histone H3, | en |
| dc.relation.page | 78 | |
| dc.identifier.doi | 10.6342/NTU201701793 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-07-24 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生命科學系 | zh_TW |
| 顯示於系所單位： | 生命科學系 | |
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