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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 江伯倫(Bor-Luen Chiang) | |
| dc.contributor.author | Pei-Shiuan Wu | en |
| dc.contributor.author | 吳佩璇 | zh_TW |
| dc.date.accessioned | 2023-03-19T21:10:33Z | - |
| dc.date.copyright | 2022-10-05 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-08-29 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/83561 | - |
| dc.description.abstract | 乾癬(Psoriasis)為常見的慢性皮膚發炎病變的疾病，由於免疫失調或是乾癬易感性基因誘發表皮細胞生長速度增加、角化不全及脫屑等現象，且會併發乾癬性關節炎等，嚴重影響患者的生活品質。過去研究發現T細胞族群中的17型T輔助細胞(Th17 cells)在乾癬發病中扮演重要角色，其免疫機制由炎性髓樣樹突狀細胞 (inflammatory myeloid dendritic cells)釋放介白素23(interleukin-23, IL-23)與Th17 cells作用，從而產生豐富的促發炎細胞因子造成皮膚發炎，如: IL-17、干擾素-γ (interferon-γ, IFN-γ)、腫瘤壞死因子(tumor necrosis factor, TNF)和IL-22。且目前已有IL-23、IL-17A單株抗體藥物對乾癬的皮膚和關節產生實質性的有益反應，如:Tildrakizumab和Secukinumab等藥物。隨著治療乾癬的分子和遺傳病理機制不斷被闡明，藥物也不斷地被開發，但口服或注射所造成的副作用相對局部應用大，因此我們想利用潛在的免疫治療靶點進行研究與開發局部siRNA塗抹的藥物。我們的研究將針對造成乾癬重要的Th17細胞的轉錄因子為RAR-related orphan receptor γ t (RORγt)作為治療靶點，利用慢病毒載體遞送siRNA 進入皮膚內進行基因沉默，藉此減少Th17細胞的分化及IL-17等細胞因子的生成來達到治療的效果。由我們的研究結果證實了針對RORγt的siRNA在體外的功性，確認其siRNA序列能有效抑制IL-23/IL-17軸的訊息路徑，而後利用水凝膠及帶有針對RORγt的siRNA慢病毒載體塗抹至乾癬小鼠進行治療，由皮膚切片及促發炎基因表現量中顯示有不錯的治療效果。在未來的研究，我們將選擇微針 (microneedle)更具生物相容性的方式，將此siRNA遞送入皮下進行局部治療，這將會是個新興的治療方式。 | zh_TW |
| dc.description.abstract | Psoriasis is mediated by the immune cells which pro-inflammatory cell lineage mainly is T helper 17 cells (Th17 cells). Th17 cells produced abundant inflammatory cytokines by myeloid dendritic cells, such as IL-17, IFN-γ, TNF and IL-22. Currently, the drug development of monoclonal antibodies against IL-17 and IL-23 including Secukinumab and Tildrakizumab. However, oral administration or injection can cause more side effects. Therefore, we want to use potential immunotherapeutic targets for research and development of siRNA drugs for topical application. We aimed to target the retinoic acid-receptor-related orphan receptor (RORγt) transcription factor of Th17 cells through the siRNA against RORγt deliver into the skin via lentiviral vector. It can reduce the differentiation of Th17 cells and the production of pro-inflammatory cytokines such as IL-17 to achieve therapeutic effects. Therefore, our study confirmed the functionality of the siRNA targeting RORγt in vitro, and has a significant therapeutic effect in the imiquimod (IMQ) induced psoriasis model. In the future, we will choose a more biocompatible way of microneedles to delivery siRNA into the subcutaneous for topical treatment. It might become a novel therapeutic modality for psoriasis. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-19T21:10:33Z (GMT). No. of bitstreams: 1 U0001-2408202215392100.pdf: 5153950 bytes, checksum: 13df48b00e0d5c12067f12797ce4d73e (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | 口試委員審定書 I 致謝 II 中文摘要 IV ABSTRACT V TABLE OF CONTENTS VI TABLE OF FIGURES XI I. INTRODUCTION 1 1. Psoriasis 2 1.1 Characterization of psoriasis 2 1.2 Genetic inheritance and immune response are the most critical pathogenic factors in psoriasis 4 1.3 The therapeutic strategy of psoriasis 5 1.4 The animal model of psoriasis 6 2. RAR-related orphan receptor gamma t (RORγt) 8 2.1 Immunomodulatory function of RORγt 8 2.2 RORγt as therapeutic approach 9 3. RNA interference (RNAi) 9 4. Hypothesis and specific aim 10 II. MATERIAL AND METHOD 12 5. Materials 13 5.1 Mice 13 5.2 Isolation and activation of murine primary thymocytes 13 5.3 Flow cytometry 14 5.4 RNA extraction 15 5.5 Reverse transcription-polymerase chain reaction (RT-PCR) 15 5.6 Quantitative real-time PCR 15 5.7 Escherichia coli (E. coli) bacterial culturing and DNA extraction kit 17 5.8 Agarose gel electrophoresis, restriction enzyme and buffer 17 5.9 Preparation of shRNA-encoding lentivirus 17 5.10 The lentiviral titer was assessed by qPCR lentivirus titration kit 18 5.11 Determination of the cell viability by mIL-7 18 5.12 Determination of cytokine production by ELISA 18 5.13 Imiquimod-induced psoriasis model 18 5.14 Treatment of imiquimod-induced psoriasis model 19 5.15 Western blot 19 5.16 IHC staining 20 5.17 Mouse Th17 cell differentiation 20 6. Methods 20 6.1 Isolation of thymocytes from mice 20 6.2 Thymocytes activation 21 6.3 Analysis of RORγt expression in thymocytes by flow cytometry 21 6.4 RNA extraction 22 6.5 cDNA synthesis and quantitative real-time PCR 22 6.6 Plasmids prepared from E. coli bacteria 23 6.7 Plasmid DNA purification from E. coli by DNA extraction kit 23 6.8 Digesting DNA fragments with restriction enzymes 24 6.9 Agarose gel electrophoresis for the separation of DNA fragments 24 6.10 Selecting RNA target sites and sequencing 25 6.11 Packaging shRNA-encoding lentivirus 25 6.12 The lentiviral titer was assessed by qPCR lentivirus titration kit 26 6.13 Investigation of mouse IL-7 on the viability of activated thymocytes 26 6.14 Determination of transfection efficiency by eGFP-lentivirus in thymocytes 27 6.15Determination of suppressed efficiency of RORγt in thymocytes 27 6.16 Imiquimod (IMQ)-induced psoriasis model 27 6.17 Determination of Psoriasis Area Severity Index (PASI) score system and bodyweight 28 6.18 Th17 differentiation 29 6.19 Determination of suppressed efficiency of IL-23/IL-17 axis pathway in Th17 cells 29 6.20 Application of GFP-lentivirus with hydrogel to skin for IMQ model 30 6.21 Application of siRORγt-3-lentivirus with hydrogel to skin for IMQ model 31 III. RESULTS 32 1. Lentiviral production and transfection of packaging plasmids 33 1.1 Construction of plasmids and cloning information 33 1.2 Gel electrophoresis bands to determine DNA sizes of lentiviral transfer plasmids 33 2. Lentivirus containing siRNA against RORγt reduced RORγt expression in thymocytes 34 2.1 The high expression levels of RORγt in thymocytes from five to seven week-old BALB/c mice 34 2.2 Lentivirus containing siRNA against RORγt reduced RORγt production and mRNA level 34 2.3 IL-7 promote the suppressive effects of siRNA against RORγt in thymocytes 35 3. Imiquimod (IMQ) - induced psoriasis model 36 3.1 Flow chart of imiquimod (IMQ) - induced psoriasis model 36 3.2 Imiquimod (IMQ) - induced psoriasis typically caused psoriatic dermatopathology 36 3.3 Imiquimod (IMQ)-induced psoriasis induced systemic inflammatory reaction 37 4. Th17 cells of IMQ-treated mice produced more pro-inflammation cytokines 38 5. RORγt knockdown decreased IL-23/IL-17 axis proinflammatory signaling pathway 39 6. Applying GFP-lentivirus to psoriasis model using different matrix 40 7. Skin delivery of lentivirus containing siRNA against RORγt for the treatment of psoriasis 40 IV. DISCUSSION AND CONCLUSION 43 V. FIGURES 50 VI. REFERENCES 70 TABLE OF FIGURES Figure 1. Construction of plasmids and cloning information 51 Figure 2. Determine the size of the plasmid of the lentiviral vector by gel electrophoresis bands 52 Figure 3. High expression level of RORγt in thymocytes after treatment with anti CD3/CD28 Ab or PMA/ionomycin for 4 to 6 hours 53 Figure 4. The suppressive effects of siRORγt were reduced the RORγt expression 54 Figure 5. IL-7 promotes cell viability and transfection efficiency in thymocytes 55 Figure 6. IL-7 promote the suppressive effects of siRNA against RORγt in thymocytes 56 Figure 7. Flow chart of imiquimod (IMQ)-induced psoriasis model 57 Figure 8. The Psoriasis Area Severity Index (PASI) measured severity of skin inflammation and detected changes in body weight 58 Figure 9. Imiquimod (IMQ)-induced psoriasis typically caused psoriatic dermatopathology and induced pro-inflammation cytokine production in skin 59 Figure 10. Imiquimod (IMQ)-induced psoriasis induced systemic inflammatory reaction 60 Figure 11. Th17 cells of IMQ-treated psoriasis mice produced more proinflammatory cytokines after treatment PMA/ionomycin for 4 hours 62 Figure 12. RORγt knockdown suppressed IL-23/IL-17 axis proinflammatory signaling pathway 63 Figure 13. Applying different matrices including PBS, oil, hydrogel and mixed with GFP-lentivirus for IMQ-induced psoriasis model 64 Figure 14 Therapeutics targeting RORγt via lentiviral gene delivery in skin of IMQ induced psoriasis to inhibit the IL-23/IL-17 pathway 67 | |
| dc.language.iso | en | |
| dc.subject | 17 型T 輔助細胞 | zh_TW |
| dc.subject | 乾癬 | zh_TW |
| dc.subject | 慢病毒載體 | zh_TW |
| dc.subject | 治療 | zh_TW |
| dc.subject | 基因沉默 | zh_TW |
| dc.subject | Therapy | en |
| dc.subject | Lentivirus vector | en |
| dc.subject | T helper 17 cells | en |
| dc.subject | Gene silencing | en |
| dc.subject | Psoriasis | en |
| dc.title | RORγt 的siRNA 在乾癬動物模型的治療應用 | zh_TW |
| dc.title | Therapeutic application of siRNA against RORγt in animal model of psoriasis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 繆希椿(Shi-Chuen Miaw),何佳安(Ja-An Annie Ho) | |
| dc.subject.keyword | 乾癬,17 型T 輔助細胞,慢病毒載體,基因沉默,治療, | zh_TW |
| dc.subject.keyword | Psoriasis,T helper 17 cells,Lentivirus vector,Therapy,Gene silencing, | en |
| dc.relation.page | 81 | |
| dc.identifier.doi | 10.6342/NTU202202766 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2022-08-30 | |
| 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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