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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 游舒涵 | zh_TW |
| dc.contributor.advisor | Shu-Han Yu | en |
| dc.contributor.author | 尤韋傑 | zh_TW |
| dc.contributor.author | WEI-CHIEH Yu | en |
| dc.date.accessioned | 2023-08-15T16:22:01Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-08-15 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-07-31 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/88452 | - |
| dc.description.abstract | 不明原因性特發性肺纖維化 (Idiopathic Pulmonary Fibrosis) 直至目前無法被完全治癒，且病情的進展難以控制，容易造成肺功能持續的惡化，並導致高致死率。「泛組蛋白去乙醯化酶抑制劑」 (Pan HDAC Inhibitor)，例如Suberoylanilide Hydroxamic acid (SAHA)，雖然已經顯示出減緩肺纖維化進程的潛力，但由於是會抑制所有的組蛋白去乙醯化酶，存在靶向外的效應，進而造成許多像是肝、皮膚毒性副作用。因此，具有選擇性的「組蛋白去乙醯化酶抑制劑 (HDAC Inhibitor)」對於減少副作用是有益的，且能較精準地延緩甚至治癒疾病。為了實現這一目標，我們與台大藥學系余兆武老師合作，設計並合成了24種新的HDAC6、HDAC8或雙重HDAC6/8抑制劑，並建立了一個三階段篩選平台，以快速篩選出能夠有效緩解TGF-β1誘導肺纖維化的HDAC抑制劑。這個三階段篩選平台包括小鼠NIH-3T3胚胎纖維母細胞預篩檢作為第一階段、人類肺纖維母細胞（HPF）篩檢作為第二階段。第三階段，則是使用撲類惡注射劑 (Bleomycin) 引發肺纖維化小鼠模型評估領導藥物的預防肺纖維化效果。在第一階段中，從24個合成HDAC抑制劑中，篩選後共得到五個命中藥物 (Hit Compounds)，然後在第二階段中，同時使用人類肺纖維母細胞作為篩選模型並且對五個命中藥物進行Caco-2通透性 (Permeability) 和肝微粒體穩定性 (Liver Microsomal stability) 測試，最終得到了兩個領導化合物 (Lead Compound)。進一步在第三階段中，通過肺纖維化小鼠模型確效兩個領導化合物的抗纖維化作用。這兩個領導化合物能有效抑制TGF-β1誘導的肺纖維細胞增殖和纖維化相關蛋白表現，進而減緩肺纖維化的進程。這一創新的三階段篩選平台將加速發現和降低開發緩解TGF-β1誘導的肺纖維化HDAC抑制劑的成本。此外，選擇性HDAC抑制劑的應用將有助於開發更有效且無毒副作用的藥物，這將有望改善特發性肺纖維化患者的生活質量。 | zh_TW |
| dc.description.abstract | Idiopathic pulmonary fibrosis of unknown etiology cannot be completely cured, and the progression of the disease is difficult to control, leading to a high mortality rate and continuous deterioration of lung function. Although histone deacetylase inhibitors (HDAC inhibitors) such as suberoylanilide hydroxamic acid (SAHA), a pan HDAC inhibitor, have shown potential in slowing the progression of pulmonary fibrosis, they have non-specific effects on all histone deacetylase enzymes, resulting in many side effects such as liver and kidney toxicity. Therefore, selective HDAC inhibitors can be beneficial in reducing side effects and more precisely delaying or even curing pulmonary fibrosis. To achieve this goal, we collaborated with Dr. Chao-Wu Yu at the National Taiwan University School of Pharmacy to design and synthesize twenty-four new HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a three-stage screening platform to quickly identify HDAC inhibitors that can effectively alleviate TGF-β1-induced pulmonary fibrosis.
This three-stage screening platform was employed to evaluate potential drugs for their preventive effect on pulmonary fibrosis. In the first stage, NIH-3T3 mouse embryonic fibroblasts served as the pre-screening model, leading to the identification of five hit compounds out of 24 synthesized HDAC inhibitors. Subsequently, the second stage utilized human pulmonary fibroblasts (HPF) as the screening model, and two leading compounds were selected based on permeability and liver microsomal stability tests. Lastly, the anti-fibrotic effects of the two leading compounds were confirmed in the mouse model of induced pulmonary fibrosis through bleomycin injection in the third stage. These two leading compounds can effectively inhibit TGF-β1-induced pulmonary fibroblast proliferation and fibrosis-related protein expression, thereby slowing the progression of pulmonary fibrosis. This innovative three-stage screening platform will accelerate the discovery and reduce the development costs of HDAC inhibitors for alleviating TGF-β1-induced pulmonary fibrosis. In addition, the application of selective HDAC inhibitors will help develop more effective and less toxic drugs, which is expected to improve the quality of life of patients with idiopathic pulmonary fibrosis. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-08-15T16:22:01Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-08-15T16:22:01Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | ACKNOWLEDGMENT I
摘要 IV ABSTRACT VI TABLE OF CONTENT VIII LIST OF FIGURES XIII LIST OF APPENDIX TABLES XVIII I. INTRODUCTION 1 1.1 Idiopathic Pulmonary Fibrosis 1 1.2 The Current Treatment of Pulmonary Fibrosis 2 1.3 Histone Deacetylase (HDAC) 4 1.4 Transforming Growth Factor-β (TGF-β) 4 1.5 Histone Deacetylase (HDAC) Inhibitors 5 II. Literature Review 8 III. Specific Aims 9 IV. Material and Methods 10 4.1 First Stage NIH-3T3 Screening Platform 10 4.1.1 NIH-3T3 Mouse Fibroblasts Culture 10 4.1.2 Cell IC50 11 4.1.3 TGF-β1 Stimulation of Fibroblasts 12 4.1.4 Assay for Fibroblast Proliferation 13 4.1.5 Western Blotting 14 4.1.6 Real-Time Quantitative PCR 15 4.2 Second Stage HPF Screening Platform 17 4.2.1 Human Pulmonary Fibroblasts (HPFs) Culture 17 4.2.2 A549 Culture 18 4.2.3 Testing HDACi Compound Stability Using Human Liver Microsomes 18 4.2.4 Evaluation of HDACi Compound Membrane Permeability Using Caco-2 Cells… 19 4.3 Third Stage Bleomycin-Induced Lung Fibrosis Mouse In Vivo Test 21 4.3.1 Bleomycin-Induced Lung Fibrosis Mouse Model 21 4.3.2 Pulmonary Function Assessment 21 4.3.3 Histology Assay 22 V. Results 22 5.1 First-Stage NIH-3T3 High-Throughput Drug Screening 22 5.1.1 Assessing the Effectiveness of HDAC Inhibitor Compounds Developed In-House.. …22 5.1.2 Development of TGF-β1-Induced Fibrosis Proliferation Model: The Initial Stage Mouse NIH-3T3 Fibroblast Prescreen Platform 23 5.1.3 Assessment of NIH-3T3 Fibroblast Viability and Toxicity through HDACi IC50 Values 24 5.1.4 Assessing the Effect of HDACi on NIH-3T3 Cell Proliferation 25 5.1.5 Identification of Hit Compounds 15, 16, 17, 20, and 21 through Immunoblotting and qRT-PCR Analysis 26 5.1.6 Effects of Hit Compounds on Activity and Expression Levels of HDAC 6/8 Isoforms 27 5.2 The Second Stage of Drug Screening Through Human Pulmonary Fibroblast (Certain aspects of the experimental procedures and methodologies were referenced in the Material and Methods of the first stage NIH-3T3 screening platform) 29 5.2.1 The Second Stage of Screening: Human Pulmonary Fibroblasts (HPFs) and IC50 Values for Five Selected Hit Compounds 29 5.2.2 Inhibition of TGF-β1-induced HPF Proliferation by the Five Hit Compounds 30 5.2.3 Superior Anti-Fibrosis Effects of Compounds 15, 16, and 20 Revealed by HPF Model Immunoblotting and qRT-PCR Analysis 31 5.2.4 Testing Stability and Permeability of Hit Compounds 32 5.2.5 Discovery of Promising Non-Hydroxamic Acid Analogues from HDAC Inhibitor 15 for Therapeutic Development 33 5.3 The Third-Stage In Vivo Test Through Bleomycin-Induced Lung Fibrosis Mouse Model 35 5.3.1 Bleomycin Dose Validation 35 5.3.2 Anti-Fibrosis Effects Test of Lead Compounds Through Bleomycin-Induced Lung Fibrosis Mouse Model 38 VI. CONCLUSIONS 40 VII. DISCUSSION 43 VIII. PERSPECTIVES 50 VI. APPENDIX 105 VII. CURRICULUM VITAE 111 VIII. REFERENCES 114 | - |
| dc.language.iso | en | - |
| dc.subject | 不明原因性肺纖維化 | zh_TW |
| dc.subject | 組蛋白去乙醯化酶 | zh_TW |
| dc.subject | 人類肺纖維母細胞 | zh_TW |
| dc.subject | 小分子藥物篩選 | zh_TW |
| dc.subject | 乙型轉化生長因子 | zh_TW |
| dc.subject | 撲類惡注射劑引發小鼠肺纖維化動物模型 | zh_TW |
| dc.subject | bleomycin-induced mouse pulmonary fibrosis model | en |
| dc.subject | transforming growth factor-β | en |
| dc.subject | human lung fibroblasts | en |
| dc.subject | histone deacetylase | en |
| dc.subject | Idiopathic pulmonary fibrosis | en |
| dc.subject | small molecule screening | en |
| dc.title | 開發三階段肺纖維化藥物篩選模型，篩選HDAC6、HDAC8和HDAC6/8抑制劑用於治療TGF-β1誘導的特發性肺纖維化 | zh_TW |
| dc.title | Establishment of a three-stage platform to screen for newly synthesized HDAC6, HDAC8, and HDAC6/8 inhibitors against TGF-β1-induced idiopathic pulmonary fibrosis | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 林水龍;林劭品;陳靜宜;余兆武 | zh_TW |
| dc.contributor.oralexamcommittee | Shuei-Liong Lin;Shau-Ping Lin;Ching-Yi Chen;Chao-Wu Yu | en |
| dc.subject.keyword | 不明原因性肺纖維化,組蛋白去乙醯化酶,小分子藥物篩選,乙型轉化生長因子,人類肺纖維母細胞,撲類惡注射劑引發小鼠肺纖維化動物模型, | zh_TW |
| dc.subject.keyword | Idiopathic pulmonary fibrosis,histone deacetylase,small molecule screening,transforming growth factor-β,human lung fibroblasts,bleomycin-induced mouse pulmonary fibrosis model, | en |
| dc.relation.page | 125 | - |
| dc.identifier.doi | 10.6342/NTU202302255 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2023-08-02 | - |
| dc.contributor.author-college | 生物資源暨農學院 | - |
| dc.contributor.author-dept | 生物科技研究所 | - |
| dc.date.embargo-lift | 2028-07-27 | - |
| 顯示於系所單位： | 生物科技研究所 | |
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