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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 廖述朗(Shu-Lang Liao) | |
dc.contributor.author | Chih-Wei Shih | en |
dc.contributor.author | 施智偉 | zh_TW |
dc.date.accessioned | 2021-06-08T02:55:47Z | - |
dc.date.copyright | 2017-09-12 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-03 | |
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'Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' orbitopathy: a randomized controlled study', J Clin Endocrinol Metab, 100: 422-31. Smith, T. J., and L. Hegedus. 2016. 'Graves' Disease', N Engl J Med, 375: 1552-65. Song, X., Y. Li, X. Chen, G. Yin, Q. Huang, Y. Chen, G. Xu, and L. Wang. 2014. 'bFGF promotes adipocyte differentiation in human mesenchymal stem cells derived from embryonic stem cells', Genet Mol Biol, 37: 127-34. Stan, M. N., J. A. Garrity, B. G. Carranza Leon, T. Prabin, E. A. Bradley, and R. S. Bahn. 2015. 'Randomized controlled trial of rituximab in patients with Graves' orbitopathy', J Clin Endocrinol Metab, 100: 432-41. Sung Mo Kang, So Yeon Lee. 2013. 'Effects of PDGF-BB and b-FGF on the production of cytokines, hyaluronic acid and the proliferation of orbital fibroblasts in thyroid ophthalmopathy', molcular and cellular toxicology, 9: 195-202. Thomas, J., L. Gregory, and B. Louis. 2005. Orbit, eyelid, and lacrimal system. . van Steensel, L., and W. A. Dik. 2010. 'The orbital fibroblast: a key player and target for therapy in graves' ophthalmopathy', Orbit, 29: 202-6. Virakul, S., J. W. Heutz, V. A. Dalm, R. P. Peeters, D. Paridaens, W. A. van den Bosch, N. Hirankarn, P. M. van Hagen, and W. A. Dik. 2016. 'Basic FGF and PDGF-BB synergistically stimulate hyaluronan and IL-6 production by orbital fibroblasts', Mol Cell Endocrinol, 433: 94-104. Wang, Y., and T. J. Smith. 2014. 'Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy', Invest Ophthalmol Vis Sci, 55: 1735-48. Yayon, A., and M. Klagsbrun. 1990. 'Autocrine regulation of cell growth and transformation by basic fibroblast growth factor', Cancer Metastasis Rev, 9: 191-202. Ye, X., J. Liu, Y. Wang, L. Bin, and J. Wang. 2014. 'Increased serum VEGF and b-FGF in Graves' ophthalmopathy', Graefes Arch Clin Exp Ophthalmol, 252: 1639-44. Young Kwang Chae1, 2, 3,*, Keerthi Ranganath3,*, Peter S. Hammerman4, Christos Vaklavas5, Nisha Mohindra1,2,3, Aparna Kalyan1,2,3, Maria Matsangou1,2,3, Ricardo Costa1, Benedito Carneiro1,2,3, Victoria M. Villa or1,2,3, Massimo Cristofanilli1,2,3 and Francis J. Giles1,2,3. 2017. 'nhibition of the broblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application', oncotarget, 8: 16052-74 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20622 | - |
dc.description.abstract | 甲狀腺眼病變是最常見的眼窩疾病,有多達半數以上的Graves’ disease 患者有眼病變。許多眼病變無法以現有治療方式治癒(例如眼藥水、全身性類固醇、眼窩放射性治療、眼窩減壓手術)。甲狀腺眼病變的症狀包括結膜充血、眼球突出、動眼肌病變、視神經病變等。這些症狀是由眼窩脂肪組織增生與動眼肌肥厚引起,而這些眼窩內組織的變化與纖維母細胞(fibroblast)有關。纖維母細胞表面受體受到特定細胞因子刺激後,可以製造琉璃醣碳基酸(hyaluronic acid)與前列腺素衍生物素(prostanoids),也可以增生和分化成脂肪細胞與肌纖維母細胞。這些能夠刺激纖維母細胞的細胞因子包括thyroid-stimulating immunoglobulins,interleukin-6 (IL-6), IL-8,和prostaglandin E2 (PGE2)等。纖維母細胞生長因子(fibroblast growth factor, FGF)也能影響纖維母細胞的表現,但它在甲狀腺眼疾的研究中較少被提及,角色也較不明確。本研究希望可以釐清纖維母細胞生長因子、纖維母細胞與甲狀腺眼病變之間的相關性,並測纖維母細胞生長因子受體(fibroblast growth factor receptor, FGFR) 抑制劑是否可能影響纖維母細胞而推測它是否可能用來治療甲狀腺眼病變。
我們的實驗方法是收集血液樣本,包括甲狀腺眼患者(31位)與Graves’ disease 而無眼病變患者(24位),測量血中纖維母細胞生長因子、甲狀腺功能、甲促素受體抗體等指數以比較照分析。我們也收集兩群眼窩纖維母細胞,分別來分別來自甲狀腺眼疾(31位)與非甲狀腺眼疾(34位)受試者的眼窩組織,從中分離出纖維母細胞。用western blot與reverse transcription quantitative PCR (RT-qPCR)來測試FGFR mRNA的表現量。我們使用Hs68上皮纖維母細胞株測試FGF1,與FGFR抑制劑 (AZD4547, BGJ398,和SUS5402) 對於Hs68細胞生長與分化的影響。 關於實驗結果,在血液樣本的部分,甲狀腺眼病變病患與Graves’ disease 而無眼病變患者相較,血液中的FGF1濃度較高(中位數19.18 pg/mL v.s. 7.06pg/mL, P=0.025)。用western blot探測FGFR可以發現甲狀腺眼疾與非甲狀腺眼疾兩組病患的眼窩纖維母細胞均表現出較多的FGFR1,與非常少量的FGFR2,3,4,但表現在兩組間並無明顯差異。用RT-qPCR則可發現甲狀腺眼疾與非甲狀腺眼疾兩組病患的眼窩纖維母細胞都表現出較多的FGFR1 mRNA,與少量的FGFR2,3,4 mRNA,其表現量在兩組間也沒有明顯的差異。在Hs68細胞株上,可以發現FGF1有促進Hs68細胞生長與分化為脂肪細胞的作用。另外,FGF1有抑制Hs68分化為肌纖維母細胞的作用。我們測試了FGFR抑制對細胞生長和分化的影響。其中AZD4547和BGJ398可以拮抗FGF1對於促進Hs68生長的作用。AZD4547和BGJ398可以拮抗FGF1抑制Hs68分化為肌纖維母細胞的影響。 我們的實驗對於FGF和眼窩纖維母細胞在甲狀腺眼疾的致病機轉提供了初步的資訊,FGF對纖維母細胞的的生長與分化有一定的調控角色。我們也發現FGFR抑制劑可以抑制眼窩纖維母細胞的增生,FGFR抑制劑可能是一個新的治療甲狀腺眼疾的方法。但仍然有許多主題需要進一步釐清,例如FGF對於Hs68細胞株生長分化的影響能否在受試者眼窩纖維母細胞上表現,FGFR抑制劑對眼窩纖維母細胞分化的影響也需要進一步研究來確定。藉由這些相關的研究,我們才能對甲狀腺眼疾的致病機轉與治療更加瞭解。 | zh_TW |
dc.description.abstract | Thyroid eye disease (TED) is the most common orbital disease. Oophthalmopathy is seen in up to 50% more than half of the patients with Graves’ disease. Many patients with TED can’t tolerate or be cured by current treatments including topical ophthalmic medications, systemic steroid, orbital radiotherapy and orbital decompression surgery. Clinical signs of TED include conjunctival injection, proptosis, eyelid retraction, restrictive extraocular myopathy, and compressive optic neuropathy. These signs are mainly caused by exraocular muscle hypertrophy and expanded orbital adipose tissue. Orbital fibroblasts play a major role in the pathogenesis of TED. When stimulated by thyroid-stimulating immunoglobulins and other cytokines, for example, interlukin-6, ilterlukin-8, and prostaglandin E2, orbital fibroblasts can produce hyaluronic acid and inflammatory prostanoids, they can also proliferate or differentiate into adipocytes. Fibroblast growth factors (FGFs), when binding to FGF receptors (FGFRs) on the fibroblasts, may also have some effect on cell proliferation and differentiation. However, the role of FGFs in TED is unclear. In this study, we investigate the relationship of FGF, fibroblast and TED. We also observe the influence of FGFR inhibitors on orbital fibroblasts.
Serum samples were collected from patients with TED (31 patients) and Graves’ disease without orbitopathy (24 patients). Levels of FGF, thyrotropin, thyroxin, thyrotropin binding inhibitory immunoglobulin (TBII) were measured and analyzed. Orbital fibroblasts were isolated from orbital tissue, which was obtained from orbital surgeries due to TED (31 patients) and other diseases (34 patients). FGFRs of orbital fibroblasts were observed by western blot and expression of FGFR mRNA were measured by RT-qPCR. We evaluate the effect of FGF1 and FGFR inhibitors (AZD4547, BGJ398, and SUS5402) on Hs68 fibroblast cell line. Cell proliferation, adipogenic differentiation and myofibroblastic differentiation were observed and measured. Serum FGF1 was higher in cases of TED than in Graves’ disease without orbitopathy (19.18 pg/mL v.s. 7.06pg/mL, p=0.025). Abundant FGFR1 and very low level of FGFR2,3,4 of orbital fibroblasts were revealed by western blot in TED and non-TED patients. There was no significant difference of FGFRs expression between TED and non-TED patients. In the result of RT-qPCR, there was abundant expression of FGFR1 mRNA and low level of FGFR2,3,4 mRNA in TED and non-TED patients. There was no difference of FGFR mRNA expression between TED and non-TED groups. In Hs68 cells, FGF1 promoted cell proliferation and adipogenic differentiation. We also observed that FGF1 inhibited fibroblastic differentiation in Hs68 cells. AZD4547 and BGJ398 could antagonize the effect of FGF1 on fibroblasts proliferation and myofibroblastic differentiation. Our study provides preliminary information about the role of FGF on orbital fibroblasts in TED. We also observed that FGFR inhibitors could inhibit orbital fibroblast proliferation. FGF-FGFR pathway could be a new treatment target for TED in the future. Further studies are needed, for example, the effect of FGF on orbital fibroblasts, the effect of FGFR inhibitors on orbital fibroblasts. We could understand more about the pathogenesis and treatment of TED through further studies on FGF. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:55:47Z (GMT). No. of bitstreams: 1 ntu-106-P04421005-1.pdf: 5129098 bytes, checksum: 9e8161517e803a6c782c3922cbe185c4 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 口試委員會審定書......1
誌謝......4 中文摘要......5 英文摘要......7 1.Introduction......9 1.1 Thyroid eye disease (TED) is the most common orbital disorder......9 1.2 There are limitations of current treatments for TED......11 1.3 Fibroblasts play a major role in the pathogenesis of TED......12 1.4 Fibroblast growth factor (FGF) in serum and orbital tissue increases in TED......14 1.5 Purposes......16 1.6 Hypothesis......17 2. Materials and methods......17 2.1 Fibroblast samples......17 2.2 Blood samples......18 2.3 FGFR measurement......18 2.4 Fibroblast proliferation......18 2.5 Myofibroblastic differentiation......19 2.6 Adipogenesis......20 2.7 Statistical analysis......20 3.Results......20 3.1 Serum FGF in Graves’ disease with and without orbitopathy......21 3.2 FGFR of orbital fibroblast......21 3.3 Influences of FGF and FGFR inhibitors on Hs68......22 3.3.1 FGF1, FGFR inhibitors and fibroblast proliferation......22 3.3.2 FGF, FGFR inhibitors and myofibroblastic differentiation......22 3.3.3 FGF and Adipogenesis......22 4.Discussion......22 4.1 Serum FGF and TED......22 4.2 FGFR expression in orbital fibroblasts......24 4.3 FGF1 induces fibroblast proliferation and adipogenesis......24 4.4 FGF1 could inhibit myofibroblastic differentiation......25 4.5 FGFR inhibitors......27 4.6 Roles of FGF in TED......28 5. Further studies......29 5.1 Subtypes of fibroblast and TED......29 5.2 Investigate the role of FGFR inhibitors on adipogenic differentiation ......29 5.3 Apply the study to orbital fibroblasts......29 5.4 Searching for appropriate FGFR inhibitors to treat TED......30 6. References......30 7. Summary......33 8. Figures and Tables......35 Figure 1. Western blot of FGFR......35 Figure 2. Results of RT-qPCR for FGFR1,2,3,4 mRNA in orbital fibroblasts of TED and control group......36 Figure 3. Hs68 proliferation by MTT assay......36 Figure 4. Myofibroblastic differentiation of Hs68 at 48 hours......37 Figure 5. Hs68 myofibroblastic differentiation......37 Figure 6. Adipogenesis of Hs68 cells at 10 days......38 Figure 7. Oil red O intensity of Hs68 cells in control and cells with FGF1 stimulation......38 Table 1. Werner’s classification of the severity of Graves’ orbitopathy......39 Table 2. Clinical activity score of Graves’ orbitopathy......39 Table 3. EUGOGO’s classification of the severity of Graves’ orbitopathy......39 Table 4. Responses of orbital fibroblast to factors involve in TED......40 Table 5. Primer codes for RT-qPCR......40 Table 6. Characteristics and blood test results of TED patients (Group 1) and Graves’ disease without orbitopathy (Group 2)......40 Table 7. Relationship of TED and serum level of FGF1, TSH, free T4, and TBII using univariate logistic regression model......41 Table 8. Multivariate regression model of TED and age, sex, and blood tests…...41 Table 9. Characteristics of TED and non-TED patients......41 Table 10. Relationship of TED and FGFR and FGFR mRNA......41 | |
dc.language.iso | zh-TW | |
dc.title | 纖維母細胞生長因子對甲狀腺眼病變病患眼內纖維母細胞的影響 | zh_TW |
dc.title | Influences of fibroblast growth factor on orbital fibroblast in thyroid eye disease | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 楊偉勛(Wei-Shiung Yang),蔡丰喬(Feng-Chiao Tsai) | |
dc.subject.keyword | 甲狀腺眼病變,纖維母細胞生長因子,纖維母細胞,纖維母細胞受體,葛雷夫氏症, | zh_TW |
dc.subject.keyword | Thyroid eye disease,Fibroblast growth factor,Fibroblast,Fibroblast growth factor receptor,Graves’ disease, | en |
dc.relation.page | 41 | |
dc.identifier.doi | 10.6342/NTU201702502 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-08-04 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
顯示於系所單位: | 臨床醫學研究所 |
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