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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐立中(Li-Chung Hsu) | |
| dc.contributor.author | Yi-Shan Chien | en |
| dc.contributor.author | 簡懿姍 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:13:54Z | - |
| dc.date.available | 2024-08-28 | |
| dc.date.copyright | 2019-08-28 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-07-31 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78711 | - |
| dc.description.abstract | 在先天性免疫系統中，發炎小體(Inflammasome)是一群蛋白質複合體扮演著清除外來病原體或組織損傷的關鍵角色。活化的發炎小體將誘發第一型半胱天冬酶(caspase-1)自剪切而激活，並以其酵素活性剪切第一型介白素IL-1β及IL-18等細胞激素成為具有生物活性的型態。此外，第一型半胱天冬酶亦可剪切活化穿孔蛋白Gasdermin D (GSDMD)進而導致發炎性細胞凋亡，稱為細胞焦亡(pyroptosis)。
本篇研究發現一個核醣核酸解旋脢27(DDX27) 在NLRP3發炎小體活化過程作為一個負向調節的角色。我們在人類巨噬細胞THP-1細胞株或小鼠骨髓來源巨噬細胞中抑制或減少表現DDX27能增強NLRP3發炎小體活化誘發之第一型半胱天冬酶活化及IL-1β產生。並發現在巨噬細胞分別處以類鐸受體激活劑，細菌內毒素脂多醣體 (LPS)或 Pam3CSK4後皆能促使DDX27自細胞核移動至細胞質，進而阻止NLRP3在預備活化過程與粒線體表面心脂（cardiolipin）的結合。爾後在NLRP3第二級活化訊號刺激下DDX27蛋白質量減少而使NLRP3發炎小體得以組裝。 此外，Ddx27基因剔除（Ddx27-/-）小鼠具有胚胎致死性。接著我們在Ddx27基因半剔除（Ddx27+/-）及條件式Ddx27剔除小鼠（Ddx27F/F:Mx1-Cre）中證實在抑制DDX27表現的動物模式施打尿酸鹽結晶（MSU）將會引發更嚴重之腹膜炎或痛風關節炎等發炎反應。 總結DDX27是以調節NLRP3移動至粒線體表面及活化的機制在NLRP3發炎小體活化過程作為一個負向調控的角色，可能作為未來針對發炎小體相關疾病進行精準治療的標的。 粒線體被認為是NLRP3發炎小體組裝活化的平台，然而位於其上之調控機制尚未全然了解。為了查明粒線體如何參與NLRP3發炎小體活化調控及其機制，我們分別產製了野生型與Nlrp3剔除之小鼠不朽化骨髓細胞，並以反轉錄病毒系統在細胞植入用以分離純化粒線體的表位標記，擬利用質譜儀分析比較給予NLRP3發炎小體活化訊號前後之巨噬細胞在各組別位於粒線體的蛋白質體與代謝體組成變化。並期望能發現潛在參與調控NLRP3發炎小體活化的成分，並進一部探討可能用以未來針對發炎小體相關疾病進行精準治療的標的。 | zh_TW |
| dc.description.abstract | The inflammasome, an emerging multi-protein complex, plays a crucial role in the clearance of microbial pathogens and tissue repair. Activation of the inflammasome results in the activation of caspase-1, which subsequently cleaves precursors of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 into their bioactive forms. In addition, caspase-1 can trigger a type of inflammatory cell death, named pyroptosis. Among the characterized inflammasomes, NLRP3 inflammasome is the most studied inflammasome, and dysregulation of NLRP3 inflammasome activation has been linked to numerous human diseases including auto-inflammatory diseases, cancers, and diabetes. Thus, the mechanisms underlying the regulation of the NLRP3 inflammasomes have been extensively investigated. However, most studies have focused on initiation of NLRP3 inflammasome assembly and activation, while its negative regulation remains unclear.
We previous identified a novel DEAD-box RNA helicase, DDX27, which negatively regulated the NLRP3 inflammasome activation. In this study, we continue to study the underlying mechanism by which DDX27 regulates NLRP3 activation and its physiological function. We found that LPS or Pam3CSK4 induced DDX27 translocation from the nucleus to the cytoplasm where it associated with NLRP3 and suppressed the translocation of NLRP3 to mitochondria by competing its binding to mitochondrial cardiolipin. Heterozygous deletion or interferon-responsive conditional knockout of Ddx27 mice exhibited more severe monosodium urate-induced inflammatory responses. indicated DDX27 as a negative regulator of NLRP3 inflammasome and might be a potential therapeutic target for the treatments of NLRP3 inflammasome-associated diseases. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:13:54Z (GMT). No. of bitstreams: 1 ntu-108-R06448005-1.pdf: 3334630 bytes, checksum: 7d39dd4ef07ce713851d3d461b97b426 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | Contents
口試委員會審定書 I 中文摘要 II Abstract IV Contents VI Introduction 1 1. The innate immune system and Pattern recognition receptors 1 2. Inflammasomes 2 3. NLR family pyrin domain containing 3 (NLRP3) 3 4. Activation of NLRP3 inflammasome 4 5. Critical intracellular locations for NLRP3 activation 6 6. Regulation of NLRP3 inflammasome activation 7 7. DEAD-box RNA helicase protein family 8 8. DEAD-box protein 27 (DDX27) 8 Specific Aim 10 Materials and methods 11 1. Reagents 11 2. Mice 12 3. Plasmids 13 4. Cell culture 15 5. Preparation of mouse bone marrow derived macrophages (BMDMs) 16 6. Immortalization of mouse bone marrow derived macrophages 17 7. Lentivirus production 18 8. Retrovirus production 18 9. Immunoblotting 19 10. Detection of secreted cytokines and caspase-1 20 11. Immunofluorescence 21 12. Quantitative RT PCR (q-RTPCR) 22 13. Preparation of nuclear and cytosolic fractions 23 14. In vitro Liposome binding assay 24 15. Preparation of Monosodium Urate (MSU) crystals 25 16. Mouse MSU-induced Peritonitis model 26 17. Mouse MSU-induced Gout model 26 18. Enzyme-Linked Immunosorbent Assays (ELISA) 27 19. Flow cytometry (FACS) 28 21. Mitochondrial isolation 29 22. Statistical Analysis 30 Table 1. Primers for mouse genotyping 31 Table 2. Primary Antibodies for Immunoblotting 32 Table 3. Secondary Antibodies for Immunoblotting and Immunostaining 33 Table 4. Primers for qPCR 34 Results 35 | |
| dc.language.iso | en | |
| dc.title | 嶄新的發炎小體調控機制 | zh_TW |
| dc.title | Novel regulatory mechanisms of NLRP3 inflammasome activation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林琬琬(Wan-Wan Lin),楊性芳(Hsin-Fang Yang-Yen) | |
| dc.subject.keyword | 核糖核酸解旋?27,NLRP3發炎小體,粒腺體,痛風,腹膜炎, | zh_TW |
| dc.subject.keyword | DDX27,NLRP3 inflammasome,mitochondria,gout,peritonitis, | en |
| dc.relation.page | 96 | |
| dc.identifier.doi | 10.6342/NTU201902185 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-07-31 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| dc.date.embargo-lift | 2024-08-28 | - |
| 顯示於系所單位： | 分子醫學研究所 | |
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