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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林辰栖 | zh_TW |
| dc.contributor.advisor | Chen-Si Lin | en |
| dc.contributor.author | 胡詠琪 | zh_TW |
| dc.contributor.author | Yung-Chi Hu | en |
| dc.date.accessioned | 2026-04-30T16:10:01Z | - |
| dc.date.available | 2026-05-01 | - |
| dc.date.copyright | 2026-04-30 | - |
| dc.date.issued | 2026 | - |
| dc.date.submitted | 2026-03-26 | - |
| dc.identifier.citation | 1. Zhao, M. et al. Targeting fibrosis: mechanisms and clinical trials. Signal transduction and targeted therapy 7, 206 (2022).
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Eckschlager, T., Plch, J., Stiborova, M. & Hrabeta, J. Histone deacetylase inhibitors as anticancer drugs. International journal of molecular sciences 18, 1414 (2017). 41. Li, Y. & Seto, E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb Perspect Med 6 (2016). https://doi.org/10.1101/cshperspect.a026831 42. Marks, P. A. Histone deacetylase inhibitors: a chemical genetics approach to understanding cellular functions. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms 1799, 717-725 (2010). 43. Seane, E. N., Nair, S., Vandevoorde, C. & Joubert, A. Mechanistic Sequence of Histone Deacetylase Inhibitors and Radiation Treatment: An Overview. Pharmaceuticals 17, 602 (2024). 44. Xu, W.-S., Parmigiani, R. B. & Marks, P. A. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26, 5541-5552 (2007). 45. Zhang, J. & Zhong, Q. Histone deacetylase inhibitors and cell death. Cellular and molecular life sciences 71, 3885-3901 (2014). 46. Hrgovic, I. et al. Histone deacetylase inhibitors interfere with angiogenesis by decreasing endothelial VEGFR‐2 protein half‐life in part via a VE‐cadherin‐dependent mechanism. Experimental dermatology 26, 194-201 (2017). 47. Ellis, L., Hammers, H. & Pili, R. Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer letters 280, 145-153 (2009). 48. Marks, P. A. The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert opinion on investigational drugs 19, 1049-1066 (2010). 49. Robert, C. & Rassool, F. V. HDAC inhibitors: roles of DNA damage and repair. Advances in cancer research 116, 87-129 (2012). 50. Li, X. et al. HDAC inhibition potentiates anti-tumor activity of macrophages and enhances anti-PD-L1-mediated tumor suppression. Oncogene 40, 1836-1850 (2021). 51. Bondarev, A. D. et al. Recent developments of HDAC inhibitors: Emerging indications and novel molecules. British journal of clinical pharmacology 87, 4577-4597 (2021). 52. El Omari, N. et al. Clinical efficacy and mechanistic insights of FDA-approved HDAC inhibitors in the treatment of lymphoma. European Journal of Pharmaceutical Sciences, 107057 (2025). 53. DeAngelo, D. J. et al. Phase II trial of panobinostat, an oral pan‐deacetylase inhibitor in patients with primary myelofibrosis, post–essential thrombocythaemia, and post–polycythaemia vera myelofibrosis. British journal of haematology 162, 326-335 (2013). 54. Peled, A., Zipori, D., Abramsky, O., Ovadia, H. & Shezen, E. Expression of alpha-smooth muscle actin in murine bone marrow stromal cells. (1991). 55. Rahman, M. F.-U. et al. Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm. Nature Communications 13, 5347 (2022). 56. Rai, S. et al. Inhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm. Nature Communications 13, 5346 (2022). 57. Aguirre, L. E. et al. Triple-negative myelofibrosis: disease features, response to treatment and outcomes. Clinical Lymphoma Myeloma and Leukemia 24, 459-467 (2024). 58. Teodorescu, P. et al. Transforming growth factor β‐mediated micromechanics modulates disease progression in primary myelofibrosis. Journal of Cellular and Molecular Medicine 24, 11100-11110 (2020). 59. Gaspar-Maia, A., Alajem, A., Meshorer, E. & Ramalho-Santos, M. Open chromatin in pluripotency and reprogramming. Nature reviews Molecular cell biology 12, 36-47 (2011). 60. Lyu, X., Hu, M., Peng, J., Zhang, X. & Sanders, Y. Y. HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis. Therapeutic advances in chronic disease 10, 2040622319862697 (2019). 61. Zhang, L. X. et al. Transgenic overexpression of active HDAC4 in the heart attenuates cardiac function and exacerbates remodeling in infarcted myocardium. Journal of Applied Physiology 125, 1968-1978 (2018). 62. Shen, F. et al. Pharmacological and genetic inhibition of HDAC4 alleviates renal injury and fibrosis in mice. Frontiers in Pharmacology 13, 929334 (2022). 63. Adapala, V. J., Adedokun, S. A., Considine, R. V. & Ajuwon, K. M. Acute inflammation plays a limited role in the regulation of adipose tissue COL1A1 protein abundance. The Journal of nutritional biochemistry 23, 567-572 (2012). 64. Hara, M. et al. Periostin promotes fibroblast migration and inhibits muscle repair after skeletal muscle injury. JBJS 100, e108 (2018). 65. Li, Y. H., Woo, S. H., Choi, D. H. & Cho, E.-H. Succinate causes α-SMA production through GPR91 activation in hepatic stellate cells. Biochemical and biophysical research communications 463, 853-858 (2015). 66. Chen, W. et al. Dynamics of elastin in liver fibrosis: accumulates late during progression and degrades slowly in regression. Journal of cellular physiology 234, 22613-22622 (2019). 67. Naik, P. K. et al. Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. American Journal of Physiology-Lung Cellular and Molecular Physiology 303, L1046-L1056 (2012). 68. Xie, W.-B. et al. Smad2 and myocardin-related transcription factor B cooperatively regulate vascular smooth muscle differentiation from neural crest cells. Circulation research 113, e76-e86 (2013). 69. Huang, S. et al. The role of Smad2 and Smad3 in regulating homeostatic functions of fibroblasts in vitro and in adult mice. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1867, 118703 (2020). 70. Tang, B. et al. Silica's silent threat: Contributing to skin fibrosis in systemic sclerosis by targeting the HDAC4/Smad2/3 pathway. Environmental Pollution 355, 124194 (2024). | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/102276 | - |
| dc.description.abstract | 骨髓纖維化（Myelofibrosis, MF）是一種骨髓增生性腫瘤（myeloproliferative neoplasm）。其特徵為骨髓基質的結構異常及網狀纖維與膠原纖維的過度沉積，導致骨髓微環境受損。由於受損骨髓中造血功能障礙，患者常出現貧血與因髓外造血所引起的肝脾腫大，進一步影響生活品質。此外，骨髓微環境的改變亦為惡性造血細胞提供有利的生存環境，使部分患者進一步演變為急性骨髓性白血病（acute myeloid leukemia, AML），大幅降低其存活率。目前的治療策略主要聚焦於緩解全身性症狀，但對於骨髓纖維化的抑制或逆轉效果有限。愈來愈多研究顯示，組蛋白去乙醯化酶（histone deacetylases, HDACs）可透過調控細胞骨架結構，並下調抗纖維化與促凋亡基因的表達，促進纖維化。此外，MF患者的HDAC表現量顯著高於健康個體，HDAC抑制劑（HDAC inhibitors, HDACis）被認為具有潛在的治療價值，可用以逆轉MF病理狀態。因此，本研究旨在探討一種新型HDAC抑制劑在MF治療中的潛力及其作用機制。我們使用小鼠骨髓來源的纖維母細胞樣基質細胞OP9與M2-10B4，使其在TGF-β刺激下，表現出增殖速率上升與膠原蛋白合成增加的現象，模擬纖維化狀態。結果顯示，此新型HDAC抑制劑cpd15可成功誘導組蛋白乙醯化及細胞凋亡、抑制膠原蛋白與細胞外基質形成。根據蛋白質體分析，cpd15能促進抗纖維化路徑及抑制促纖維化路徑表現，同時具有改善發炎微環境、增加細胞清除活性氧的能力，使其微環境不利於纖維化發展以發揮抗纖維化作用，顯示其具逆轉纖維化之潛力，為MF治療帶來新的契機。 | zh_TW |
| dc.description.abstract | Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by the alteration of the bone marrow stroma and the excessive accumulation of reticulin and collagen fibers, leading to impaired bone marrow microenvironment. Due to impaired hematopoiesis in the damaged bone marrow, patients develop anemia and extramedullary hematopoiesis–induced hepatosplenomegaly, ultimately compromising their quality of life. Moreover, the altered bone marrow microenvironment creates a more favorable niche for malignant hematopoietic cells, predisposing some patients to progression to acute myeloid leukemia (AML), which significantly reduces survival rates. Current therapeutic strategies primarily aim to alleviate systemic symptoms but fail to effectively target or reverse bone marrow fibrosis. Accumulating evidence suggests that histone deacetylases (HDACs) promote fibrotic processes by influencing cytoskeletal organization and downregulating anti-fibrotic and pro-apoptotic gene expression. Furthermore, MF patients exhibit significantly elevated HDAC expression levels compared to healthy individuals, suggesting that HDAC inhibitors (HDACis) may have the potential for reversing MF. Thus, this study aims to investigate the therapeutic potential and underlying mechanisms of a novel HDACi in MF treatment. Two murine bone marrow–derived fibroblast-like stroma cell lines, OP9 and M2-10B4, were used in this study. TGF-β was added to the culture medium to stimulate these cells, resulting in increased proliferative capacity and enhanced collagen synthesis, thereby establishing an in vitro model that recapitulates a fibrotic phenotype. Our results demonstrated that the novel HDAC inhibitor cpd15 effectively induced histone acetylation, promoted apoptosis, and suppressed the expression of collagen and extracellular matrix–associated genes. Proteomic analysis further revealed that cpd15 upregulated anti-fibrotic signaling pathways while concurrently downregulating pro-fibrotic pathways. In addition, cpd15 improved the inflammatory microenvironment and enhanced cellular reactive oxygen species (ROS) scavenging capacity, thereby creating a milieu unfavorable for fibrotic progression. Collectively, these findings suggest that cpd15 exerts anti-fibrotic effects and holds the potential to reverse fibrosis, providing a promising therapeutic strategy for MF. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2026-04-30T16:10:01Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2026-04-30T16:10:01Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract ii Contents iv List of Tables vii List of Figures viii Chapter 1 Introduction 1 1.1 Fibrosis 1 1.2 Myelofibrosis (MF) 3 1.2.1 Myelofibrosis (MF) 3 1.2.2 The symptom of MF 3 1.2.3 Diagnosis of myelofibrosis 4 1.2.4 Pathogenesis of Myelofibrosis 5 1.2.5 Current treatment of Myelofibrosis 6 1.3 Histone deacetylases (HDACs) 7 1.3.1 Histone acetylation 7 1.3.2 The classification of Histone acetylases (HDACs) 8 1.3.3 HDAC in disease 9 1.3.4 HDAC inhibitor and Mechanism 10 1.3.5 Approved HDACi 15 1.4 Rationale for this study 19 Chapter 2 Material and Method 20 2.1 Study design 20 2.2 Cell culture and chemical source 20 2.3 Protein extraction 21 2.4 Western blot 22 2.5 RNA extraction, cDNA synthesis and qPCR 23 2.6 Cell viability assay 24 2.7 TGF-β induced fibrosis 24 2.8 Cell apoptosis assay 25 2.9 Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis 26 2.10 Statistical analysis 27 Chapter 3 Result 28 3.1 TGF-β can induce cell proliferation and differentiation in bone marrow–derived fibroblast-like stroma cell 28 3.2 TGF-β induce cell differentiation and collagen formation in bone marrow–derived fibroblast-like stroma cell 29 3.3 Novel HDACi can inhibit cell viability bone marrow–derived fibroblast-like stroma cell 30 3.4 cpd15 can promote cell apoptosis 30 3.5 cpd15 can inhibit collagen and ECM formation induced by TGF-β in bone marrow–derived fibroblast-like stroma cell 31 3.6 cpd15 can increase histone acetylation in bone marrow–derived fibroblast-like stroma cell 32 3.7 cpd15 can reduce inflammation in bone marrow–derived fibroblast-like stroma cell 33 3.8 cpd15 can inhibit TGF-β/Smad signaling pathway in bone marrow–derived fibroblast-like stroma cell 33 3.9 The anti-fibrotic mechanism of cpd15 34 Chapter 4 Discussion 37 Tables 40 Figures 57 Reference 70 | - |
| dc.language.iso | en | - |
| dc.subject | 骨髓增生性腫瘤 | - |
| dc.subject | 骨髓纖維化 | - |
| dc.subject | 組蛋白去乙醯化酶抑制劑 | - |
| dc.subject | 轉化生長因子-β | - |
| dc.subject | 骨髓基質細胞 | - |
| dc.subject | Myeloproliferative neoplasms (MPN) | - |
| dc.subject | Myelofibrosis (MF) | - |
| dc.subject | Histone deacetylases (HDACs) | - |
| dc.subject | Transforming growth factor-beta (TGF-β) | - |
| dc.subject | Bone marrow stroma cells | - |
| dc.title | 新型組蛋白去乙醯化酶抑制劑在骨髓纖維化中的治療潛力與作用機制 | zh_TW |
| dc.title | Exploring the Therapeutic Efficacy and Mechanistic Action of Novel HDAC Inhibitors in Myelofibrosis | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 114-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 廖泰慶;邱亦涵 | zh_TW |
| dc.contributor.oralexamcommittee | Albert T Liao;Yi-Han Chiu | en |
| dc.subject.keyword | 骨髓增生性腫瘤,骨髓纖維化組蛋白去乙醯化酶抑制劑轉化生長因子-β骨髓基質細胞 | zh_TW |
| dc.subject.keyword | Myeloproliferative neoplasms (MPN),Myelofibrosis (MF)Histone deacetylases (HDACs)Transforming growth factor-beta (TGF-β)Bone marrow stroma cells | en |
| dc.relation.page | 74 | - |
| dc.identifier.doi | 10.6342/NTU202600768 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2026-03-26 | - |
| dc.contributor.author-college | 生物資源暨農學院 | - |
| dc.contributor.author-dept | 獸醫學系 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 獸醫學系 | |
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