請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64819
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 廖述朗 | |
dc.contributor.author | Man sim cheng | en |
dc.contributor.author | 鄭敏蟬 | zh_TW |
dc.date.accessioned | 2021-06-16T23:00:04Z | - |
dc.date.available | 2012-09-19 | |
dc.date.copyright | 2012-09-19 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-07 | |
dc.identifier.citation | Alevizaki M, Mantzou E, Cimponeriu A, Saltiki K, Philippou G, Wiersinga W. The Pro 12 Ala PPAR gamma gene polymorphism: possible modifier of the activity and severity of thyroid-associated orbitopathy (TAO). Clin Endocrinol (Oxf). 2009 Mar;70(3):464-8. Epub 2008 Jul 7.
Allahabadia A, Heward JM, Nithiyananthan R, Gibson SM, Reuser TT, Dodson PM, Franklyn JA, Gough SC. MHC class II region, CTLA4 gene, and ophthalmopathy in patients with Graves' disease. Lancet. 2001 Sep 22;358(9286):984-5. Aniszewski JP, Valyasevi RW, Bahn RS.Relationship between disease duration and predominant orbital T cell subset in Graves' ophthalmopathy.J Clin Endocrinol Metab. 2000 Feb;85(2):776-80. Antonelli A, Rotondi M, Ferrari SM, Fallahi P, Romagnani P, Franceschini SS, Serio M, Ferrannini E. Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves' ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists. J Clin Endocrinol Metab. 2006 Feb;91(2):614-20. Arnold R, and Konig W. Peroxisome-proliferator-activated receptor-gamma agonists inhibit the release of proinflammatory cytokines from RSV-infected epithelial cells. Virology. 2006;346:427-39. Bahn RS, Dutton CM, Natt N, Joba W, Spitzweg C, and Heufelder AE. Thyrotropin receptor expression in Graves' orbital adipose/connective tissues: potential autoantigen in Graves' ophthalmopathy. J Clin Endocrinol Metab. 1998;83:998-1002. Bahn RS, Heufelder AE Pathogenesis of Graves' ophthalmopathy. New England Journal of Medicine. 1993 Nov 11;329(20):1468-75 Bahn RS, Dutton CM, Natt N, Joba W, Spitzweg C, Heufelder AE.Thyrotropin receptor expression in Graves' orbital adipose/connective tissues: potential autoantigen in Graves' ophthalmopathy. J Clin Endocrinol Metab. 1998 Mar;83(3):998-1002. Cao HJ, Wang HS, Zhang Y, Lin HY, Phipps RP, Smith TJ. Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression. Insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy. J Biol Chem. 1998 Nov 6;273(45):29615-25. Cawood TJ, Moriarty P, O'Farrelly C, O'Shea D.The effects of tumour necrosis factor-alpha and interleukin1 on an in vitro model of thyroid-associated ophthalmopathy; contrasting effects on adipogenesis.Eur J Endocrinol. 2006 Sep;155(3):395-403. Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation.2000 Oct;49(10):497-505. Clark RB. The role of PPARs in inflammation and immunity. J Leukoc Biol. 2002;71:388-400. Daniels CE, Wilkes MC, Edens M, Kottom TJ, Murphy SJ, Limper AH, Leof EB. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis.J Clin Invest. 2004 Nov;114(9):1308-16. Daynes RA, and Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol. 2002;2:748-59. Derynck R, Zhang Y, Feng XH.Smads: transcriptional activators of TGF-beta responses.Cell. 1998 Dec 11;95(6):737-40. Dik WA, McAnulty RJ, Versnel MA, Naber BA, Zimmermann LJ, Laurent GJ, Mutsaers SE. Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats. Thorax. 2003 Sep;58(9):765-71. Douglas RS, Gianoukakis AG, Kamat S, Smith TJ.Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves' disease may carry functional consequences for disease pathogenesis.J Immunol. 2007 Mar 1;178(5):3281-7. Dunlop ME, and Muggli EE. Hyaluronan increases glomerular cyclooxygenase-2 protein expression in a p38 MAP-kinase-dependent process. Kidney Int. 2002;61:1729-38. Ellis I, Banyard J, Schor SL. Differential response of fetal and adult fibroblasts to cytokines: cell migration and hyaluronan synthesis.Development. 1997 Apr;124(8):1593-600. Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889-95. Feldon SE, Park DJ, O'Loughlin CW, Nguyen VT, Landskroner-Eiger S, Chang D, Thatcher TH, Phipps RP.Autologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves' ophthalmopathy.Invest Ophthalmol Vis Sci. 2005 Nov;46(11):3913-21. Feldon SE, O'loughlin CW, Ray DM, Landskroner-Eiger S, Seweryniak KE, Phipps RP.Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes.Am J Pathol. 2006 Oct;169(4):1183-93. Ferguson HE, Kulkarni A, Lehmann GM, Garcia-Bates TM, Thatcher TH, Huxlin KR, Phipps RP, Sime PJ. Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts.Am J Respir Cell Mol Biol. 2009 Dec;41(6):722-30. Epub 2009 Mar 13. Förster G, Otto E, Hansen C, Ochs K, Kahaly G. Analysis of orbital T cells in thyroid-associated ophthalmopathy. Clin Exp Immunol. 1998 Jun;112(3):427-34. Fu M, Zhang J, Zhu X, Myles DE, Willson TM, Liu X, Chen YE. Peroxisome proliferator-activated receptor gamma inhibits transforming growth factor beta-induced connective tissue growth factor expression in human aortic smooth muscle cells by interfering with Smad3. J Biol Chem. 2001 Dec 7;276(49):45888-94. Epub 2001 Oct 5. Garrity JA, Bahn RS.Pathogenesis of graves ophthalmopathy: implications for prediction, prevention, and treatment.Am J Ophthalmol. 2006 Jul;142(1):147-153 Gerding MN, van der Meer JW, Broenink M, Bakker O, Wiersinga WM, Prummel MF.Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy.Clin Endocrinol (Oxf). 2000 Mar;52(3):267-71. Ghosh AK, Bhattacharyya S, Lakos G, Chen SJ, Mori Y, and Varga J. Disruption of transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor gamma. Arthritis Rheum. 2004;50:1305-18. Gianoukakis AG, Khadavi N, Smith TJ.Cytokines, Graves' disease, and thyroid-associated ophthalmopathy.Thyroid. 2008 Sep;18(9):953-8. Guo N, Woeller CF, Feldon SE, Phipps RP. Peroxisome proliferator-activated receptor gamma ligands inhibit transforming growth factor-beta-induced, hyaluronan-dependent, T cell adhesion to orbital fibroblasts.J Biol Chem. 2011 May 27;286(21):18856-67. Han R, Tsui S, Smith TJ. Up-regulation of prostaglandin E2 synthesis by interleukin-1beta in human orbital fibroblasts involves coordinate induction of prostaglandin-endoperoxide H synthase-2 and glutathione-dependent prostaglandin E2 synthase expression. J Biol Chem. 2002 May 10;277(19):16355-64. Epub 2002 Feb 14. Hayashida T, Poncelet AC, Hubchak SC, Schnaper HW.TGF-beta1 activates MAP kinase in human mesangial cells: a possible role in collagen expression.Kidney Int. 1999 Nov;56(5):1710-20. Heufelder AE, Bahn RS.Detection and localization of cytokine immunoreactivity in retro-ocular connective tissue in Graves' ophthalmopathy. Eur J Clin Invest. 1993. Jan;23(1):10-7 Hufnagel TJ, Hickey WF, Cobbs WH, Jakobiec FA, Iwamoto T, Eagle RC.Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with Graves' disease.Ophthalmology. 1984 Nov;91(11):1411-9. Itano N, Kimata K.Expression cloning and molecular characterization of HAS protein, a eukaryotic hyaluronan synthase.J Biol Chem. 1996 Apr 26;271(17):9875-8. Inoki K, Haneda M, Ishida T, Mori H, Maeda S, Koya D, Sugimoto T, Kikkawa R.Role of mitogen-activated protein kinases as downstream effectors of transforming growth factor-beta in mesangial cells.Kidney Int Suppl. 2000 Sep;77:S76-80. Kaback LA, and Smith TJ. Expression of hyaluronan synthase messenger ribonucleic acids and their induction by interleukin-1beta in human orbital fibroblasts: potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 1999;84:4079-84. Kahaly G, Hansen C, Felke B, and Dienes HP. Immunohistochemical staining of retrobulbar adipose tissue in Graves' ophthalmopathy. Clin Immunol Immunopathol. 1994;73:53-62. Kähäri VM, Olsen DR, Rhudy RW, Carrillo P, Chen YQ, Uitto J.Transforming growth factor-beta up-regulates elastin gene expression in human skin fibroblasts. Evidence for post-transcriptional modulation.Lab Invest. 1992 May;66(5):580-8 Kazim M, Goldberg RA, Smith TJ.Insights into the pathogenesis of thyroid-associated orbitopathy: evolving rationale for therapy. Arch Ophthalmol. 2002 Mar;120(3):380-6. Koumas L, Smith TJ, Feldon S, Blumberg N, Phipps RP. Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. Am J Pathol. 2003 Oct;163(4):1291-300. Khoo TK, Bahn RS. Pathogenesis of Graves' ophthalmopathy: the role of autoantibodies. Thyroid. 2007 Oct;17(10):1013-8. Kumar S, Coenen MJ, Scherer PE, Bahn RS. Evidence for enhanced adipogenesis in the orbits of patients with Graves' ophthalmopathy.J Clin Endocrinol Metab. 2004 Feb;89(2):930-5. Kumar S, Leontovich A, Coenen MJ, Bahn RS.Gene expression profiling of orbital adipose tissue from patients with Graves' ophthalmopathy: a potential role for secreted frizzled-related protein-1 in orbital adipogenesis.J Clin Endocrinol Metab. 2005 Aug;90(8):4730-5. Epub 2005 May 10. Lantz M, Vondrichova T, Parikh H, Frenander C, Ridderstråle M, Asman P, Aberg M, Groop L, Hallengren B. Overexpression of immediate early genes in active Graves' ophthalmopathy. J Clin Endocrinol Metab. 2005 Aug;90(8):4784-91. Laurent TC, Fraser JR.Hyaluronan.FASEB J. 1992 Apr;6(7):2397-404. Lee, Cheng-Wen.Gene expression and immunohistochemical study of orbital fat, extraocular muscle, and orbicularis oculi muscle in acute and chronic Graves’ ophthalmopathy-Insight to substitutive therapy for Graves’ ophthalmopathy.National Digital Library of Theses and Dissertations in Taiwan, 2007. Ludgate M, Crisp M, Lane C, Costagliola S, Vassart G, Weetman A, Daunerie C, and Many MC. The thyrotropin receptor in thyroid eye disease. Thyroid. 1998;8:411-3. Weetman AP. Graves' disease. N Engl J Med. 2000;343:1236-48. Mansen A, Guardiola-Diaz H, Rafter J, Branting C, and Gustafsson JA. Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa. Biochem Biophys Res Commun. 1996;222:844-51. Marinò M, Chiovato L, Lisi S, Altea MA, Marcocci C, Pinchera A.Role of thyroglobulin in the pathogenesis of Graves' ophthalmopathy: the hypothesis of Kriss revisited.J Endocrinol Invest. 2004 Mar;27(3):230-6. Marx N, Sukhova G, Murphy C, Libby P, and Plutzky J. Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am J Pathol. 1998;153:17-23. Mimura LY, Villares SM, Monteiro ML, Guazzelli IC, and Bloise W. Peroxisome proliferator-activated receptor-gamma gene expression in orbital adipose/connective tissues is increased during the active stage of Graves' ophthalmopathy. Thyroid. 2003;13:845-50. Miyazono K, ten Dijke P, and Heldin CH. TGF-beta signaling by Smad proteins. Adv Immunol. 2000;75:115-57. Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach. Br J Ophthalmol. 1989 Aug;73(8):639-44. Pan H, Chen J, Xu J, Chen M, Ma R. Antifibrotic effect by activation of peroxisome proliferator-activated receptor-gamma in corneal fibroblasts.Mol Vis. 2009 Nov 10;15:2279-86. Park BH, Vogelstein B, Kinzler KW.Genetic disruption of PPARdelta decreases the tumorigenicity of human colon cancer cells.Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2598-603. Parry CH.Enlargement of the thyroid gland in connection with enlargement or palpitation of the heart. In: Collections from the Unpublished Papers of the Late Caleb Hillier Parry. Underwood, London, 1825 pp111-129 Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves' disease and ophthalmopathy.Endocr Rev. 2003 Dec;24(6):802-35. Pritchard J, Horst N, Cruikshank W, Smith TJ.Igs from patients with Graves' disease induce the expression of T cell chemoattractants in their fibroblasts.J Immunol. 2002 Jan 15;168(2):942-50. Ricote M, Li AC, Willson TM, Kelly CJ, and Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79-82. Rodriguez-Barbero A, Dorado F, Velasco S, Pandiella A, Banas B, and Lopez-Novoa JM. TGF-beta1 induces COX-2 expression and PGE2 synthesis through MAPK and PI3K pathways in human mesangial cells. Kidney Int. 2006;70:901-9. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases. Endocr Rev. 2007 Aug;28(5):492-520. Epub 2007 May 2. Saglam F, Cavdar Z, Sarioglu S, Kolatan E, Oktay G, Yilmaz O, Camsari T. Pioglitazone reduces peritoneal fibrosis via inhibition of TGF-β, MMP-2, and MMP-9 in a model of encapsulating peritoneal sclerosis. Ren Fail. 2012;34(1):95-102. Epub 2011 Dec 5. Sempowski GD, Rozenblit J, Smith TJ, Phipps RP. Human orbital fibroblasts are activated through CD40 to induce proinflammatory cytokine production.Am J Physiol. 1998 Mar;274(3 Pt 1):C707-14. Smith TJ, Bahn RS, Gorman CA.Connective tissue, glycosaminoglycans, and diseases of the thyroid.Endocr Rev. 1989 Aug;10(3):366-91. Smith TJ, Bahn RS, Gorman CA.Hormonal regulation of hyaluronate synthesis in cultured human fibroblasts: evidence for differences between retroocular and dermal fibroblasts. J Clin Endocrinol Metab. 1989 Nov;69(5):1019-23. Smith TJ, Hoa N.Immunoglobulins from patients with Graves' disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor.J Clin Endocrinol Metab. 2004 Oct;89(10):5076-80. Smith TJ, Koumas L, Gagnon A, Bell A, Sempowski GD, Phipps RP, Sorisky A. Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy.J Clin Endocrinol Metab. 2002 Jan;87(1):385-92. Smith TJ, Wang HS, Evans CH.Leukoregulin is a potent inducer of hyaluronan synthesis in cultured human orbital fibroblasts.Am J Physiol. 1995 Feb;268(2 Pt 1):C382-8. Smith TJ, Tsai CC, Shih MJ, Tsui S, Chen B, Han R, Naik V, King CS, Press C, Kamat S, Goldberg RA, Phipps RP, Douglas RS, Gianoukakis AG.Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy.Thyroid. 2008 Sep;18(9):983-8. Starkey K, Heufelder A, Baker G, Joba W, Evans M, Davies S, Ludgate M. Peroxisome proliferator-activated receptor-gamma in thyroid eye disease: contraindication for thiazolidinedione use? J Clin Endocrinol Metab. 2003 Jan;88(1):55-9. Stern R, Asari AA, Sugahara KN.Hyaluronan fragments: an information-rich system.Eur J Cell Biol. 2006 Aug;85(8):699-715. Epub 2006 Jul 5 Straus DS, Glass CK. Cyclopentenone prostaglandins: new insights on biological activities and cellular targets. Med Res Rev. 2001 May;21(3):185-210. Sussmann M, Sarbia M, Meyer-Kirchrath J, Nusing RM, Schror K, and Fischer JW. Induction of hyaluronic acid synthase 2 (HAS2) in human vascular smooth muscle cells by vasodilatory prostaglandins. Circ Res. 2004;94:592-600. Stuhlmeier KM. Prostaglandin E2: a potent activator of hyaluronan synthase 1 in type-B-synoviocytes. Biochim Biophys Acta. 2007;1770:121-9. Tani J, Wall JR.Autoimmunity against eye-muscle antigens may explain thyroid-associated ophthalmopathy.CMAJ. 2006 Aug 1;175(3):239. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994 May 15;8(10):1224-34. Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, Gianoukakis AG, Douglas RS, Smith TJ.Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves' disease.J Immunol. 2008 Sep 15;181(6):4397-405. Usui T, Amano S, Oshika T, Suzuki K, Miyata K, Araie M, Heldin P, Yamashita H .Expression regulation of hyaluronan synthase in corneal endothelial cells.Invest Ophthalmol Vis Sci. 2000 Oct;41(11):3261-7. Valyasevi RW, Erickson DZ, Harteneck DA, Dutton CM, Heufelder AE, Jyonouchi SC, Bahn RS.Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor.J Clin Endocrinol Metab. 1999 Jul;84(7):2557-62. Vojtek AB, Cooper JA. Rho family members: activators of MAP kinase cascades.Cell. 1995 Aug 25;82(4):527-9. Wall JR. Graves' disease is a multi-system autoimmune disorder in which extra ocular muscle damage and connective tissue inflammation are variable features. Thyroid. 2002;12:35-6. Wang HS, Tung WH, Tang KT, Wong YK, Huang GJ, Wu JC, Guo YJ, and Chen CC. TGF-beta induced hyaluronan synthesis in orbital fibroblasts involves protein kinase C betaII activation in vitro. J Cell Biochem. 2005a;95:256-67. Wang W, Huang XR, Li AG, Liu F, Li JH, Truong LD, Wang XJ, and Lan HY. Signaling mechanism of TGF-beta1 in prevention of renal inflammation: role of Smad7. J Am Soc Nephrol. 2005b;16:1371-83. Weetman AP, Cohen S, Gatter KC, Fells P, Shine B.Immunohistochemical analysis of the retrobulbar tissues in Graves' ophthalmopathy.Clin Exp Immunol. 1989 Feb;75(2):222-7. Weetman AP.Graves' disease. New England Journal of Medicine. 2000 Oct 26;343(17):1236-48 Weightman DR, Perros P, Sherif IH, Kendall-Taylor P.Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy.Autoimmunity. 1993;16(4):251-7. Weigel PH, Hascall VC, Tammi M. Hyaluronan synthases.J Biol Chem. 1997 May 30;272(22):13997-4000. Wiersinga WM, Smit T, van der Gaag R, Koornneef L.Temporal relationship between onset of Graves' ophthalmopathy and onset of thyroidal Graves' disease.J Endocrinol Invest. 1988 Sep;11(8):615-9. Wiersinga WM, Bartalena L.Epidemiology and prevention of Graves' ophthalmopathy. Thyroid. 2002 Oct;12(10):855-60 Willson TM, Brown PJ, Sternbach DD, Henke BR.The PPARs: from orphan receptors to drug discovery.J Med Chem. 2000 Feb 24;43(4):527-50. Yin X, Latif R, Bahn R, Tomer Y, Davies TF.Influence of the TSH receptor gene on susceptibility to Graves' disease and Graves' ophthalmopathy.Thyroid. 2008 Nov;18(11):1201-6. Young DA, Evans CH, Smith TJ.Leukoregulin induction of protein expression in human orbital fibroblasts: evidence for anatomical site-restricted cytokine-target cell interactions.Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8904-9. Zhang L, Chawla A. Role of PPARgamma in macrophage biology and atherosclerosis.Trends Endocrinol Metab. 2004 Dec;15(10):500-5. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64819 | - |
dc.description.abstract | 研究目的:
葛瑞夫氏眼部病變是自體免疫引起的發炎反應所造成的後果。近年來研究顯示,甲狀腺刺激素受體是眼球很重要的自體抗原。典型發炎反應會引起脂肪增生和眼外肌的纖維化肥厚,從而引起眼球外凸,眼瞼發炎,以及眼周圍組織的水腫。 抗體抗原反應引發一系列的連鎖機制,包含單核白血球及巨噬細胞釋放激素。以IL-1為例子,IL-1可以引發COX-2表現,促使產生PGH2。PGH2之後轉變成PGE2,然後引起發炎反應。另一方面,PGH2可被轉變成PGD2,再經由cyclopentane ring脫水和代謝形成15d-PGJ2, 其為PPAR-γ受體的一個天然刺激原。當PPAR-γ受體活化後,可以產生抗發炎反應,同時合併脂肪增生。葛瑞夫氏眼病變有一個很特殊的組織病理學變化,葡萄醣胺類會堆積在眼球的結締組織,主要是玻尿酸的成份。最近研究顯示,眼球纖維母細胞合成玻尿酸會受到TGF-β刺激而增加。TGF-β是個與細胞生長分化有關的細胞激素。但是TGF-β過量會造成過度的疤痕組織形成以及纖維化。通過PGE2,COX-2可誘導TGF-β後產生纖維化,並激活HAS而開始堆積聚醣胺。TGF-β可增加玻尿酸形成。接著,玻尿酸和TGF-β也可以刺激COX-2和前列腺素的生成。先前研究顯示IGF-1α, IGF-1R, IL-1β, IFN-γ, PPAR-γ, TSH-R, COX-2, HAS等等物質的基因表現在葛瑞夫氏眼病變組織中都是增加的。 另一方面,PPAR-γ可破壞TGF-β信號傳導路徑,並且中斷纖維化之前的反應。這些反應可能是葛瑞夫氏眼睛病變發病機制中的一部分。在製造前列腺素PGE2和玻尿酸,或那些調節糖胺聚醣生產和脂肪分化的的途徑中,協同或拮抗作用都會發生。 本研究主要是探討細胞激素如何影響體外培養之眼窩眼外肌母細胞釋放PPAR-γ,COX-2,TGF-β,Adiponectin,CXCL10和TSH-R。本研究亦評估PPAR -γ促進劑,抑制劑和COX-2抑制劑對於眼外肌母細胞中TGF-β,玻尿酸合成酶(HAS1,HAS2,HAS3)和產生玻尿酸的影響效果。 研究方法: 我們以培養之眼外肌母細胞經IFN-γ,IGF-1,IL-1β和TNF-α刺激後,以real time PCR分析PPAR -γ,COX-2,TGF-β,CXCL10,Adiponectin,TSH- R的訊息核醣核酸(mRNA)的基因表現量。並以酶聯免疫吸附試驗(ELISA)和免疫印跡分析(Western blot)來確定TGF-β,CXCL10,COX-2,TSH-R蛋白質表現量。 此外,我們將培養之眼外肌母細胞經TNF-α刺激後,同時加入PPAR-γ促進劑、抑制劑,COX-2抑制劑,以酶聯免疫吸附試驗(ELISA)和免疫印跡分析(Western blot) 來確定TGF-β,玻尿酸合成酶(HAS1,HAS2,HAS3)和產生玻尿酸的蛋白質表現量。經由上述實驗期望可以進一步釐清葛瑞夫氏眼部病變的分子機制。 結果: 葛瑞夫氏眼病變的病人組眼外肌母細胞尤其在IL-1β或TNF-α刺激24小時下,PPAR-γ,COX-2,TGF-β,CXCL10,Adiponectin,TSH-R的訊息核醣核酸的基因表現量皆有顯著增加。TGF-β和CXCL10的酶聯免疫吸附試驗及COX-2和TSH-R的西方點墨法檢測結果和RT-PCR結果吻合。對照組則全無顯著變化。受了細胞激素刺激之後,葛瑞夫氏眼病變眼外肌母細胞基因表現的確比對照組強。在本次體外實驗的葛瑞夫氏眼病變眼外肌母細胞,COX-2抑制劑(Celecoxib)和PPAR-γ促進劑(Pioglitazone)抑制TGF-β,HAS或玻尿酸蛋白質表現未達統計上顯著,但是,我們仍然發現經由COX-2抑制劑和PPAR促進劑,有抑制TGFβ,HAS和玻尿酸表現的趨勢。我們推測玻尿酸合成增加是透過HAS基因之誘發,而這是透過TGF-β刺激所致。Celecoxib和Pioglitazone作用都可以抑制因細胞激素誘發的HAS3表現,但對HAS1或HAS2表現則無影響。TGF-β透過某種未確定的信號傳導通路來刺激HAS3表現。細胞中的玻尿酸合成可在HAS3刺激下受到誘發,這可能和葛瑞夫氏眼病變的發病有極為重要的關聯。 結論: 這些數據佐證了:細胞激素可誘導葛瑞夫氏眼部病變眼外肌母細胞表現多種基因。我們也確認了眼窩眼外肌在葛瑞夫氏眼病變的致病機制中佔很重要的角色。葛瑞夫氏眼病變自體免疫過程中,纖維母細胞以外,眼外肌應該是另一個同等重要的目標。目前的數據支持我們的假設:在葛瑞夫氏眼部病變患者的眼外肌母細胞裡,依賴COX-2的前列腺素,可以透過TGF-β訊息作用,誘導被HAS激活的玻尿酸合成反應。我們觀察到COX-2抑制劑及PPAR-γ促進劑抑制了TGF-β,HAS3和玻尿酸蛋白質的製造。未來發展中,針對葛瑞夫氏眼部病變併牽制性肌肉病變和脂肪增生,需要更多的廣泛研究以開發治療藥物。 | zh_TW |
dc.description.abstract | Purpose:
Graves’ophthalmopathy (GO) is an autoimmune inflammatory disorder.Recent evidence implicates the TSH receptor (TSH-R) as an important orbital autoantigen in GO. The characteristic clinical manifestations of GO, including proptosis, chemosis, periorbital edema, and extraocular muscle dysfunction, result from the intraorbital inflammatory process and enlargement of the adipose tissue and muscles within the orbit. After antibody binding with antigen, a cascade of inflammation starts, including monocytes and macrophages releasing cytokines, eg. IL-1β. IL-1β can induce COX-2, which can produce prostaglandin H2. After the conversion of prostaglandin H2 into prostaglandin E2, inflammation is induced. On the other hand, prostaglandin H2 can be converted to prostaglandin D2. Prostaglandin J2 is formed after dehydration of cyclopentane ring and is further metabolized to yield 15d-PGJ2, a natural ligand of PPAR-γ. After the binding of 15d-PGJ2, PPAR-γ will be activated and induce anti-inflammatory activity, combined with adipogenesis. A distinctive histopathological feature associated with GO is the accumulation of the glycosaminoglycan, mainly hyaluronan, in orbital connective tissues. In recent study, hyaluronan synthesis in orbital fibroblasts has been shown to be up-regulated by TGF-β. Overproduction of TGF-β will result in excessive scar formation and fibrosis. Through action of PGE2, COX-2 induces TGF-β and produces fibrosis, and activates HAS, starting accumulation of glycosaminoglycan. TGF-β can increase the formation of hyaluronan. In turn, hyaluronan and TGF-β can stimulate the production of COX-2 and prostaglandin. Previous study found that mRNA expression of IGF-1α, IGF-1R, IL-1β, IFN-γ, PPAR-γ, TSH-R, COX-2, HAS in GO orbital fat tissues by real time PCR were up regulated as compared to normal orbital tissues. PPAR-γ disrupts TGF-β signal transduction and blocks profibrotic responses. Some of these responses may take part in the pathogenesis of GO. Synergistic and antagonistic interactions can occur between the pathways producing prostaglandin (PGE2) and hyaluronan or those regulating glycosaminoglycan production and adipogenesis. In this study, we will investigate the effect of different cytokines on the expression of PPAR-γ, COX-2, TGF-β, Adiponectin, CXCL10, TSH-R mRNA and production of protein by myoblasts cultured from the extraocular muscles. We will also try to evaluate the effect of PPAR-γ agonist, antagonist and COX-2 inhibitor on the expression of TGF-β, hyaluronan synthase (HAS1, HAS2, HAS3) and hyaluronan. Methods: To determine whether cytokines induce these genes expression, we treated orbital myoblasts with or without IFN-γ, IGF-1, IL-1β , TNF-α. Data were analyzed by real time PCR for PPAR-γ, COX-2, TGF-β, CXCL10, Adiponectin, TSH-R mRNA. ELISA and Western blot were used to confirm the TGF-β, CXCL10, COX-2, TSH-R protein expression in cytokines treated orbital myoblasts. We cultured orbital extraocular muscles and treated them with TNF-α in the presence of the PPAR-γ agonist, antagonist and COX-2 inhibitor. ELISA and Western blot were used to determine their effect on TGF-β, hyaluronan synthase (HAS1, HAS2, HAS3) and hyaluronan protein synthesis. Results: After treating patients with Graves' ophthalmopathy group myoblasts especially in IL-1β or TNF-α for 24 hours, gene expression of the mRNA of PPAR-γ, COX-2, TGF-β, CXCL10, Adiponectin, TSH-R show significantly increase. ELISA results of TGF-β, CXCL10 and Western blot results of COX-2, TSH-R were compatable with RT-PCR. There was no significant gene expression in normal group. All myoblasts gene expressions show differences between the disease and control groups. In this in vitro experiment of cytokine treated GO myoblasts, there is a trend that the TGF-β and hyaluronan gene expression was under inhibition with COX-2 inhibitor (Celecoxib) or PPAR-γ agonist (Pioglitazone), though not reach significant level. We hypothesis that TGF-β activate hyaluronan synthesis via HAS signals. Both Celecoxib and Pioglitazone treatment inhibited cytokine induced HAS3 expression, but did not afftect HAS1 and HAS2 expression. The signaling pathways by which TGF-β regulates HAS3 are still poorly understood. HAS3 can induce hyaluronan production which may be important pathogenesis to Graves' ophthalmopathy. Conclusion: To our knowledge, this is the first in vitro experiment demonstrates PPAR-γ, COX-2, TGF-β, CXCL10, Adiponectin, TSH-R production stimulated by cytokines in GO extraocular muscles. These results suggest that the extraocular muscles indeed play an important role in GO pathogenesis besides orbital fibroblasts. Taking together, the present data did partly support our working hypothesis that COX-2 dependent PGs induce TGF-β signaling, stimulate hyaluronan production via HAS activation in GO myoblasts. In our study, we observed COX2 inhibitor and PPAR-γ agonist suppress TGF-β, HAS and hyaluronan protein production. In the future, more studies will be helpful to get useful information in the treatment of Graves’ophthalmopathy with restrictive myopathy and adipogenesis. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T23:00:04Z (GMT). No. of bitstreams: 1 ntu-101-P99421006-1.pdf: 877258 bytes, checksum: f4755bd54af8b81b4bf22ab40bc58d40 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 口試委員會審定書………………………………………………………………. 1
誌謝………………………………………………………………………………..2 中文摘要…………………………………………………………………………..3 英文摘要…………………………………………………………………………..6 碩士論文內容 第一章 研究背景及目的………………………………………………………..11 1.1 葛瑞夫氏眼睛病變簡介……………………………………………….….11 1.2 眼窩內的病理變化…………………………………………………….….12 1.3 眼窩自體抗原和葛瑞夫氏眼睛病變的致病機轉………………….…….13 1.4 免疫細胞浸潤於眼窩………………………………………………….….14 1.5 眼窩脂肪增生………………………………………………………….….15 1.6 玻尿酸堆積…………………………………………………………….….18 1.7 葛瑞夫氏眼睛病變中的細胞類型………………………………………..20 1.8 研究動機及假說…………………………………………………………..21 第二章 研究方法與材料………………………………………………………….23 2.1 患者和對照組病人之基本資料……….........………………………….…23 2.2 眼窩眼外肌細胞培養……….........…………………………….…………24 2.3 COX-2,PPAR-γ,TGF-β,CXCL10,Adiponectin,TSH-R的產量分析………………24 2.4 以RT-PCR檢測COX-2,PPAR -γ,TGF-β,CXCL10,Adiponectin和TSH-R的mRNA濃度…25 2.5 TGF-β,CXCL10的酶聯免疫吸附試驗分析…………………………….26 2.6 COX-2,TSH-R的西方點墨法分析......…………………………………..26 2.7 TGF-β和玻尿酸的酶聯免疫吸附試驗分析....…………………………….27 2.8 玻尿酸合成酶的西方點墨法分析......…………………………………….27 2.9 統計分析....………………………………………………………………...28 第三章、結果..……………………………………………………………………..29 3.1 COX-2,PPAR-γ, TGF-β, CXCL10, adiponectin, TSH-R的mRNA表現…...29 3.2 TGF-β和CXCL10的酶聯免疫吸附試驗...………………………………....30 3.3 COX-2和TSH-R的西方點墨法檢測...……………………………………..31 3.4 COX-2抑制劑,PPAR-γ促進劑抑制TGF-β和HA合成……………….......31 3.5 Celecoxib或Pioglitazone抑制HAS3合成....…...............……………………32 3.6 GW9662誘導TGF-β,HAS3和HA合成....…………………………..….....33 第四章、討論..……………………………………………………………………...34 參考文獻..…………………………………………………………………………...43 表附錄……………………………………………………………………………….53 圖附錄……………………………………………………………………………….62 | |
dc.language.iso | zh-TW | |
dc.title | "COX-2, PPAR-γ, TGF-β及各種細胞激素在甲狀腺眼外肌病變所扮演的角色" | zh_TW |
dc.title | The role of COX-2, PPAR-γ, TGF-β and different kinds of cytokines in the pathogenesis of dysthyroid myopathy | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 楊偉勛,陳偉勵 | |
dc.subject.keyword | 葛瑞夫氏眼部病變,眼窩自體抗原,細胞激素,眼窩脂肪增生,玻尿酸堆積, | zh_TW |
dc.subject.keyword | Graves’ophthalmopathy,orbital autoantigen,cytokines,orbital adipogenesis,hyaluronan deposition, | en |
dc.relation.page | 70 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-08-08 | |
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 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-101-1.pdf 目前未授權公開取用 | 856.7 kB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。