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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 江皓森 | zh_TW |
| dc.contributor.advisor | Hao-Sen Chiang | en |
| dc.contributor.author | 王柔敏 | zh_TW |
| dc.contributor.author | Jou-Min Wang | en |
| dc.date.accessioned | 2024-08-16T16:17:48Z | - |
| dc.date.available | 2024-08-17 | - |
| dc.date.copyright | 2024-08-16 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-08-12 | - |
| dc.identifier.citation | Ahluwalia, B., Moraes, L., Magnusson, M. K., & Öhman, L. (2018). Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scandinavian Journal of Gastroenterology, 53(4), 379–389. https://doi.org/10.1080/00365521.2018.1447597
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/94482 | - |
| dc.description.abstract | 發炎性腸道疾病（Inflammatory Bowel Disease, IBD）是一種胃腸道疾病，其特徵是消化道中反覆性的發炎，可以區分為克隆氏症和潰瘍性結腸炎兩類。在先天免疫系統中，嗜中性球作為抵禦感染的第一道防線，先前的研究發現嗜中性球會大量浸潤在IBD患者的腸道區域，甚至會釋放大量中性粒細胞胞外陷阱（Neutrophil extracellular traps, NETs）。此外，多白胺酸重複激酶2（Leucine-rich repeat kinase 2, LRRK2）基因的多態性已被確定為一個重要的危險因素，其在嗜中性球中的表現最高。LRRK2 是一種多功能蛋白質，具有多種酶功能，包括鳥糞嘌呤核苷三磷酸酶（GTPase）和激酶，並參與多種細胞過程，例如粒線體活性以及溶小體穩態。然而，LRRK2、嗜中性球和 IBD 之間的關係仍不清楚。
在我的研究中，我使用HL-60細胞系，並使用全反式維甲酸（all-trans retinoic acid, ATRA）或二甲基亞碸（Dimethyl sulfoxide, DMSO）作為分化劑將其分化為嗜中性球樣HL-60細胞（neutrophil-like HL-60, dHL-60），建立了研究模型。此外，我使用 LRRK2 激酶抑制劑 MLi-2 抑制 dHL-60 細胞中的 LRRK2 激酶活性，並刺激去顆粒化或中性粒細胞胞外陷阱，以研究 LRRK2 激酶活性在這兩種嗜中性球細胞功能中的作用。在我的實驗結果顯示，ATRA 和DMSO dHL-60 細胞對去顆粒化和NETs形成有不同的反應，證實與ATRA dHL-60 相比，DMSO dHL-60 是更適合研究嗜中性球功能（特別是NETs 形成）的分化模型。此外，我的研究結果表明，LRRK2 激酶活性不會影響 DMSO dHL-60 細胞去顆粒化後產生的髓過氧化物（Myeloperoxidase, MPO）的釋放。然而，在不依賴 NAPDH 氧化酶 （NOX） 的 NETosis 路徑刺激後，抑制 LRRK2 激酶活性會增加 DMSO dHL-60 細胞中擴散型 NETs 的誘導。進一步的機制研究發現當MLi-2會抑制 LRRK2 在 S935 位點及其下游蛋白 Rab10的磷酸化，在結果中也觀察到和控制組相比當LRRK2激酶活性被抑制的情況下刺激 A23187 誘導的 NETosis過程中，反而會減少組蛋白瓜氨酸化的表達。綜上所述，根據我的研究結果可以發現，LRRK2激酶活性不影響 DMSO dHL-60細胞的去顆粒化過程，但在不依賴 NOX的NETosis途徑中發揮作用，影響組蛋白瓜氨酸化。 | zh_TW |
| dc.description.abstract | Inflammatory Bowel Disease (IBD) is a gastrointestinal condition characterized by recurrent inflammation in the digestive tract, including Crohn's Disease (CD) and Ulcerative Colitis (UC). Neutrophils, as the first line of defense in the innate immune system, infiltrate the intestinal areas of IBD patients and release significant amounts of Neutrophil Extracellular Traps (NETs). The polymorphism of the Leucine-rich repeat kinase 2 (LRRK2) gene has been identified as an important risk factor, with its highest expression found in neutrophils. LRRK2 is a multifunctional protein with various enzymatic functions, including GTPase and kinase activities, involved in cellular processes such as autophagy and mitochondrial activity. However, the relationship between LRRK2, neutrophils, and IBD remains unclear.
In my study, I used the HL-60 cell line. We differentiated it into neutrophil-like HL-60 cells (dHL-60) using all-trans retinoic acid (ATRA) or Dimethyl sulfoxide (DMSO) as a differentiation agent to establish a research model. Additionally, I inhibited LRRK2 kinase activity in dHL-60 cells using the LRRK2 kinase inhibitor - MLi-2 and stimulated degranulation or NET formation to investigate the role of LRRK2 kinase activity in these neutrophil functions. My experiment results demonstrated that ATRA and DMSO dHL-60 cells responded differently to degranulation and NET formation stimuli, confirming that DMSO dHL-60 cells are a more suitable differentiation model for studying neutrophil functions, especially NET formation. Furthermore, my study showed that LRRK2 kinase activity did not affect Myeloperoxidase (MPO) release after degranulation in DMSO dHL-60 cells. However, inhibiting LRRK2 kinase activity increased the induction of spread-form NETs in the NADPH-Oxidase (NOX) - independent NETosis pathway. Further mechanistic studies revealed that MLi-2 inhibited the phosphorylation of LRRK2 at the S935 site and its downstream protein Rab10, and decreased histone citrullination during A23187-induced NETosis compared to the control group. In conclusion, our findings suggest that LRRK2 kinase activity does not impact the degranulation process in DMSO dHL-60 cells but plays a role in the NOX-independent NETosis pathway, affecting histone citrullination. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-16T16:17:48Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-16T16:17:48Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 致謝 i
中文摘要 iii Abstract v Contents vii Chapter 1 Introduction 1 1.1 Inflammatory Bowel Disease (IBD) 1 1.2 Neutrophils 1 1.2.1 Neutrophil anti-bacterial functions 2 1.2.2 Neutrophil extracellular traps (NETs) 4 1.2.3 Neutrophils in IBD 6 1.2.4 NETs in IBD 7 1.3 Leucine-Rich Repeat Kinase 2 (LRRK2) 7 1.3.1 The function of LRRK2 7 1.3.2 LRRK2 and Innate Immunity 8 1.3.3 LRRK2 kinase activity and IBD 9 1.4 HL-60 cell line model 10 1.5 Specific Aim 11 Chapter 2 Materials & Methods 13 2.1 Cell culture and differentiation 13 2.2 Quantification of HL-60 Differentiation Level 13 2.3 Degranulation 14 2.4 Simulation of NETosis 14 2.5 Detection of NETs with SYTOX green staining 15 2.6 Immunofluorescence staining 15 2.7 Quantification of NETs 16 2.8 Western blot 17 2.9 Detection of total ROS and mitochondrial ROS by plate reader 18 2.10 Data analysis 18 Chapter 3 Results 20 3.1 The optimal differentiation of HL-60 into neutrophil-like cells (dHL-60) utilizing 1 μM all-trans retinoic acid (ATRA) or 1.3% dimethyl sulfoxide (DMSO) for five days 20 3.2 Differential responses of neutrophil-like HL-60 cells differentiated with ATRA or DMSO to myeloperoxidase (MPO) release induced by cytochalasin B and N-formyl-met-leu-phe (fMLP) 21 3.3 The enzymatic activity of LRRK2 kinase has no impact on the release of MPO induced by cytochalasin B and fMLP stimulation 22 3.4 Differentiation-dependent responses of dHL-60 cells to NETosis stimuli 23 3.5 Inhibition of LRRK2 kinase activity affects NET formation in DMSO dHL-60 cells through NOX-independent NETosis pathway 25 3.6 Differential effects of LRRK2 kinase inhibition on NET formation and the phosphorylation of Rab10 in ATRA and DMSO dHL-60 27 3.7 LRRK2 kinase regulation of NET formation via histone citrullination in the NOX-independent NETosis pathway 31 Chapter 4 Discussion 34 Chapter 5 Conclusion 39 Figures 40 Figure 1. Morphological Assessment of HL-60 Cells Differentiation Level 42 Figure 2. Effected of two differentiated types of HL-60, ATRA, and DMSO, on degranulation stimulation 45 Figure 3. The activity of LRRK2 kinase did not affect the myeloperoxidase (MPO) released from DMSO dHL-60 47 Figure 4. Differential responses of dHL-60 to NET formation stimuli under various differentiation conditions 52 Figure 5. Quantification of activated SYTOX green+ cells and spread-form NETs in ATRA or DMSO dHL-60 cells with and without LRRK2 kinase inhibition 54 Figure 6. Western blot analysis of pRab10/Rab10 ratio and LRRK2 expression in ATRA and DMSO dHL-60 cells 59 Figure 7. The molecular Changes of NETosis during the inhibition of LRRK2 kinase activity 61 Figure 8. The response of differentiated HL-60 cells and the effect of LRRK2 kinase on NET formation 63 Tables 65 Table 1. Antibody list 65 Reference 66 | - |
| dc.language.iso | en | - |
| dc.subject | 發炎性腸道疾病 | zh_TW |
| dc.subject | 多白胺酸重複激酶2 | zh_TW |
| dc.subject | 嗜中性球胞外網狀結構 | zh_TW |
| dc.subject | 去顆粒化 | zh_TW |
| dc.subject | MLi-2 | zh_TW |
| dc.subject | HL-60細胞系 | zh_TW |
| dc.subject | IBD | en |
| dc.subject | HL-60 cell line | en |
| dc.subject | LRRK2 | en |
| dc.subject | NETosis | en |
| dc.subject | Degranulation | en |
| dc.subject | MLi-2 | en |
| dc.title | 利用HL-60細胞模型探討多白胺酸重複激酶2在嗜中性球功能中所參與的機制 | zh_TW |
| dc.title | Utilize the HL-60 cell model to investigate the role of LRRK2 in neutrophil functions | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 陳俊任;傅化文 | zh_TW |
| dc.contributor.oralexamcommittee | Chun-Jen Chen;Hua-Wen Fu | en |
| dc.subject.keyword | HL-60細胞系,多白胺酸重複激酶2,嗜中性球胞外網狀結構,去顆粒化,MLi-2,發炎性腸道疾病, | zh_TW |
| dc.subject.keyword | HL-60 cell line,LRRK2,NETosis,Degranulation,MLi-2,IBD, | en |
| dc.relation.page | 81 | - |
| dc.identifier.doi | 10.6342/NTU202404037 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2024-08-13 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生命科學系 | - |
| dc.date.embargo-lift | 2029-08-08 | - |
| 顯示於系所單位： | 生命科學系 | |
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