ASIC3或TRPV1基因剔除會減緩單關節炎 誘發的機械性痛覺敏感現象

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謝瑋珊(Wei-shan Hsieh) 查詢紙本館藏

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生命科學系

論文名稱

ASIC3或TRPV1基因剔除會減緩單關節炎誘發的機械性痛覺敏感現象
(Deletion of ASIC3 or TRPV1 gene reduces mono-arthritis-induced mechanical hyperalgesia)

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摘要(中)

自體免疫疾病是一個慢性的情況，起始於自體抗原的免疫功能喪失代表異質的雜亂，而去攻擊特定器官或是多種器官系統。類風溼性關節炎是一種慢性、漸進式、全身性的、特徵是關節滑膜結締組織嚴重破壞的發炎疾病。類風溼性關節炎主要涉及組織的發炎，而不是關節退變。雖然發炎會造成類風濕性關節炎病患的疼痛，但這並不是唯一造成疼痛的原因。有些病患使用抗發炎疾病修飾抗風濕性藥物治療並不能改善疼痛的情況。關節發炎通常伴隨著組織酸化。因此，酸敏感接受器對於類風溼性關節炎可能扮演關鍵角色。使用兩種基因剃除(ASIC3和TRPV1)的小鼠來研究類風溼性關節炎。每周在關節注射一次5µg CFA，連續四周，用以建立模擬類風溼性關節炎小鼠的動物模式。模擬期間測量關節寬度和關節組織病理變化，以監測關節炎的過程。以Von Frey尼龍絲來評估注射CFA後小鼠的疼痛行為反應。在野生型和基因剔除的小鼠關節注射CFA會誘發二級機械性痛覺敏感現象。ASIC3和TRPV1基因剔除的小鼠可以減緩類風溼性關節炎在後期的機械性痛覺敏感現象。

摘要(英)

Autoimmune diseases (ADs) are chronic conditions initiated by the loss of immunological tolerance to self-antigens and represent a heterogeneous group of disorders that afflict specific target organs or multiple organ systems. Rheumatoid arthritis (RA), one of ADs, can be defined as a chronic, progressive, systemic, inflammatory disease of connective tissues characterized by the severe destruction in synovial joints. RA involves primary tissue inflammation rather than joint degeneration. Although inflammation contributes to pain in RA, however, it may not be the only factor. For some patients, pain is not improved despite of the treatment with anti-inflammatory disease-modifying anti-rheumatic drugs. The aim of this thesis is to identify novel genes that are involved in RA-induced pain. Given that joint inflammation is usually accompanied by tissue acidosis, proton-sensing receptors could be the candidates for RA. Two knockout mice (ASIC3-/- & TRPV1-/-) were generated for the RA study. After intra-articular injection into a stifle joint with complete Freund’s adjuvant (CFA) once per week for 4 weeks, long-term mechanical hyperalgesia was developed in wildtype and knockout mice. Both of ASIC3-/- & TRPV1-/- reduced RA-induced mechanical hyperalgesia in the late phase.

關鍵字(中)

★ 關節炎

關鍵字(英)

★ arthritis

論文目次

第一章緒論 1
1.1自體免疫疾病(Autoimmune diseases) 2
1.1.1系統性紅斑性狼瘡(systemic lupus erythematosus；SLE) 2
1.1.2類風濕性關節炎(rheumatoid arthritis；RA) 3
1.2 類風溼性關節炎的疼痛機制 4
1.2.1 模擬類風溼性關節炎的動物模式 5
1.3 酸敏感的受體和離子通道 6
1.3.1酸敏感離子通道3(ASIC3) 6
1.3.2 辣椒素受體1(TRPV1) 6
1.3.3 TDAG8受體 (T cell death-associated gene 8) 7
1.4臨床用於治療類風濕性關節炎的藥物 8
1.5 研究動機與目的 9
第二章材料與方法 10
2.1 實驗材料 11
2.1.1 實驗動物 11
2.1.2 實驗藥品 11
2.1.3 紅斑性狼瘡( Systemic lupus erythematosus；SLE)樣品 12
2.2實驗方法 12
2.2.1小鼠基因型的判定 (Genotyping) 12
2.2.2瓊酯膠的置備及電泳分析 12
2.2.3小鼠關節炎模式 13
2.2.4 關節炎程度的評估 13
2.2.5 機械性痛覺行為實驗(Von Frey filament test) 13
2.2.6 蘇木素-伊紅染色 ( hematoxylin and eosin stain、H&E stain ) 14
2.2.7背根神經節的RNA萃取及cDNA合成 14
2.2.8紅斑性狼瘡病患血液中T細胞(CD4)的cDNA合成 15
2.2.9 定量聚合酶鏈反應 (quantitative PCR, Q-PCR) 15
2.2.10血液中cytokine定量分析ELISA( The enzyme-linked immunosorbent assay) 15
2.2.11 統計分析 (Statistics) 16
第三章結果 17
3.1 在野生型小鼠關節重複注射CFA誘發長期關節疼痛 18
3.2 組織病理學中野生型小鼠在同側腳關節的H&E染色 19
3.3 在慢性關節疼痛中酸敏感受體的基因表現 19
3.4在基因ASIC3 -/-小鼠關節連續注射CFA後，在後期減緩機械性痛覺敏感現象 20
3.5組織病理學中基因ASIC3-/-小鼠在同側腳關節的H&E染色 21
3.6在基因TRPV1-/-小鼠關節連續注射CFA後，在後期減緩關節腫脹和機械性痛覺敏感現象 21
3.7組織病理學中基因TRPV1-/-小鼠在同側腳關節的H&E染色 22
3.8測量TNF-

參考文獻

Anaya, J. M. (2012). Common mechanisms of autoimmune diseases (the autoimmune tautology). Autoimmun Rev, 11(11), 781-784. doi: 10.1016/j.autrev.2012.02.002
Arvidson, N. G., Gudbjornsson, B., Elfman, L., Ryden, A. C., Totterman, T. H., & Hallgren, R. (1994). Circadian rhythm of serum interleukin-6 in rheumatoid arthritis. Annals of the Rheumatic Diseases, 53, 521-524.
Barton, N. J., McQueen, D. S., Thomson, D., Gauldie, S. D., Wilson, A. W., Salter, D. M., & Chessell, I. P. (2006). Attenuation of experimental arthritis in TRPV1R knockout mice. Exp Mol Pathol, 81(2), 166-170. doi: 10.1016/j.yexmp.2006.04.007
Boettger, M. K., Hensellek, S., Richter, F., Gajda, M., Stockigt, R., von Banchet, G. S., . . . Schaible, H. G. (2008). Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis: evidence of a neuronal target. Arthritis Rheum, 58(8), 2368-2378. doi: 10.1002/art.23608
Boettger, M. K., Weber, K., Grossmann, D., Gajda, M., Bauer, R., Bar, K. J., . . . Schaible, H. G. (2010). Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation. Arthritis Rheum, 62(5), 1308-1318. doi: 10.1002/art.27380
Caterina, M. J., Leffler, A., Malmberg, A. B., Martin, W. J., Trafton, J., Petersen-Zeitz, K. R., . . . Julius, D. (2000). Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 288, 306-314.
Chen, Y. J., Huang, C. W., Lin, C. S., Chang, W. H., & Sun, W. H. (2009). Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain. Mol Pain, 5, 39. doi: 10.1186/1744-8069-5-39
Cheng, H. Y., & Penninger, J. M. (2004). DREAMing about arthritic pain. Ann Rheum Dis, 63 Suppl 2, ii72-ii75. doi: 10.1136/ard.2004.029942
Choi, J. W., Lee, S. Y., & Choi, Y. (1996). Identification of a putative G protein-coupled receptor induced during activation-induced apoptosis of T cells. Cellular Immunology, 168, 78–84.
Cooper, G. S., & Stroehla, B. C. (2003). The epidemiology of autoimmune diseases. Autoimmunity Reviews, 2(3), 119-125. doi: 10.1016/s1568-9972(03)00006-5
Deval, E., Gasull, X., Noel, J., Salinas, M., Baron, A., Diochot, S., & Lingueglia, E. (2010). Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol Ther, 128(3), 549-558. doi: 10.1016/j.pharmthera.2010.08.006
Dray, A. (1995). Inflammatory mediators of pain. British Journal of Anaesthesia, 75, 125–131.
Ebbinghaus, M., Uhlig, B., Richter, F., von Banchet, G. S., Gajda, M., Brauer, R., & Schaible, H. G. (2012). The role of interleukin-1beta in arthritic pain: main involvement in thermal, but not mechanical, hyperalgesia in rat antigen-induced arthritis. Arthritis Rheum, 64(12), 3897-3907. doi: 10.1002/art.34675
Emery, P., Sebba, A., & Huizinga, T. W. (2013). Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis. Ann Rheum Dis, 72(12), 1897-1904. doi: 10.1136/annrheumdis-2013-203485
Farr, M., Gravey, K., Bold, A. M., Kendall, M. J., & Bacon, P. A. (1985). Significance of the hydrogen ion concentration in synovial fluid in rheumatoid arthritis. Clinical and Experimental rheumatology, 3, 99-104.
Feldmann, M., Brennan, F. M., & Maini, R. N. (1996). Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol., 14, 397–440.
Fernandes, E. S., Russell, F. A., Spina, D., McDougall, J. J., Graepel, R., Gentry, C., . . . Brain, S. D. (2011). A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor alpha-induced inflammatory hyperalgesia and Freund′s complete adjuvant-induced monarthritis. Arthritis Rheum, 63(3), 819-829. doi: 10.1002/art.30150
Gauldie, S. D., McQueen, D. S., Clarke, C. J., & Chessell, I. P. (2004). A robust model of adjuvant-induced chronic unilateral arthritis in two mouse strains. J Neurosci Methods, 139(2), 281-291. doi: 10.1016/j.jneumeth.2004.05.003
Hang, L. H., Yang, J. P., Yin, W., Wang, L. N., Guo, F., Ji, F. H., . . . Zuo, J. L. (2012). Activation of spinal TDAG8 and its downstream PKA signaling pathway contribute to bone cancer pain in rats. Eur J Neurosci, 36(1), 2107-2117. doi: 10.1111/j.1460-9568.2012.08087.x
Helyes, Z., Szabo, A., Nemeth, J., Jakab, B., Pinter, E., Banvolgyi, A., . . . Szolcsanyi, J. (2004). Antiinflammatory and analgesic effects of somatostatin released from capsaicin-sensitive sensory nerve terminals in a Freund′s adjuvant-induced chronic arthritis model in the rat. Arthritis Rheum, 50(5), 1677-1685. doi: 10.1002/art.20184
Huang, C. W., Tzeng, J. N., Chen, Y. J., Tsai, W. F., Chen, C. C., & Sun, W. H. (2007). Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors. Mol Cell Neurosci, 36(2), 195-210. doi: 10.1016/j.mcn.2007.06.010
Ignatavicius, D. D., & MS, R., Cm. (2001). Rheumatoid arthritis and the older adult. Geriatric Nursing, 22(3), 139-142.
Ikeuchi, M., Kolker, S. J., Burnes, L. A., Walder, R. Y., & Sluka, K. A. (2008). Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice. Pain, 137(3), 662-669. doi: 10.1016/j.pain.2008.01.020
Julius, D., & Basbaum, A. I. (2001). Molecular mechanisms of nociception. Nature, 413, 203-210.
Keeble, J., Russell, F., Curtis, B., Starr, A., Pinter, E., & Brain, S. D. (2005). Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthritis Rheum, 52(10), 3248-3256. doi: 10.1002/art.21297
Kochukov, M. Y., McNearney, T. A., Fu, Y., & Westlund, K. N. (2006). Thermosensitive TRP ion channels mediate cytosolic calcium response in human synoviocytes. Am J Physiol Cell Physiol, 291(3), C424-432. doi: 10.1152/ajpcell.00553.2005
Le, L. Q., Kabarowski, J. H. S., Weng, Z., Harvill, E. T., Miller, J. F., Satterthwaite, A. B., . . . Witte, O. N. (2001). Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset
autoimmune syndrome. Immunity, 14, 561–571.
Mogi, C., Tobo, M., Tomura, H., Murata, N., He, X. D., Sato, K., . . . Okajima, F. (2009). Involvement of proton-sensing TDAG8 in extracellular acidification-induced inhibition of proinflammatory cytokine production in peritoneal macrophages. J Immunol, 182(5), 3243-3251. doi: 10.4049/jimmunol.0803466
Neugebauer, V., Han, J. S., Adwanikar, H., Fu, Y., & Ji, G. (2007). Techniques for assessing knee joint pain in arthritis. Mol Pain, 3, 8. doi: 10.1186/1744-8069-3-8
Onozawa, Y., Komai, T., & Oda, T. (2011). Activation of T cell death-associated gene 8 attenuates inflammation by negatively regulating the function of inflammatory cells. Eur J Pharmacol, 654(3), 315-319. doi: 10.1016/j.ejphar.2011.01.005
Relle, M., & Schwarting, A. (2012). Role of MHC-linked susceptibility genes in the pathogenesis of human and murine lupus. Clin Dev Immunol, 2012, 584374. doi: 10.1155/2012/584374
Scholz, J., & Woolf, C. J. (2002). Can we conquer pain? Nat Neurosci, 5 Suppl, 1062-1067. doi: 10.1038/nn942
Sluka, K. A., Rasmussen, L. A., Edgar, M. M., O′Donnell, J. M., Walder, R. Y., Kolker, S. J., . . . Firestein, G. S. (2013). Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis. Arthritis Rheum, 65(5), 1194-1202. doi: 10.1002/art.37862
Szabo, A., Helyes, Z., Sandor, K., Bite, A., Pinter, E., Nemeth, J., . . . Szolcsanyi, J. (2005). Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: in vivo study using gene-deficient mice. J Pharmacol Exp Ther, 314(1), 111-119. doi: 10.1124/jpet.104.082487
Tan, E. M., Cohen, A. S., Fries, J. F., Masi, A. T., McShane, D. J., Rothfield, N. F., . . . Winchester, R. J. (1982). The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis and Rheumatism, 25(11).
Tincani, A., Andreoli, L., Bazzani, C., Bosiso, D., & Sozzani, S. (2007). Inflammatory molecules: a target for treatment of systemic autoimmune diseases. Autoimmun Rev, 7(1), 1-7. doi: 10.1016/j.autrev.2007.03.001
Wang, J. Q., Kon, J., Mogi, C., Tobo, M., Damirin, A., Sato, K., . . . Okajima, F. (2004). TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. J Biol Chem, 279(44), 45626-45633. doi: 10.1074/jbc.M406966200

指導教授

孫維欣(Wei-hsin Sun)

審核日期

2015-6-22

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