博碩士論文 104821022 詳細資訊




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姓名 陳芊樺(Chien-Hua Chen)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 ASIC3、TRPV1或TDAG8基因缺失會減緩關節炎誘導的熱痛覺過敏並抑制衛星膠細胞表現
(ASIC3, TRPV1 or TDAG8 gene deficiency reduces arthritis-induced thermal hyperalgesia and inhibits satellite glia expression)
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摘要(中) 類風濕性關節炎是一種常見的自體免疫疾病,會造成滑液關節慢性發炎,傷害軟骨組織,導致關節毀損,常伴隨著長期性的疼痛。關節炎通常伴隨組織酸化。先前的研究中發現,酸敏感受體ASIC3、TRPV1和TDAG8可以減緩RA誘導的機械性痛覺過敏和關節發炎。然而,尚不清楚這些基因是否也參與在RA誘導的熱痛覺過敏中,以及它們是如何調節RA引發的疼痛。以前的研究表明,衛星膠細胞(SGCs)對於慢性疼痛的建立和維持扮演重要的角色,有希望成為控制病理性疼痛的目標。酸敏感受體可能會通過影響SGCs表現來調控疼痛。因此,我在小鼠關節處注射5μg的完全弗式佐劑,每週一次,連續注射四周,進行行為測試、關節炎程度分析及免疫組織化學螢光染色分析。連續注射CFA的小鼠會產生長期性的關節發炎、雙側熱痛覺過敏、減少DRG中的神經細胞和增加SGCs的數量。有趣的是,ASIC 3、TRPV 1和TDAG 8基因剔除小鼠從7~8週逆轉關節炎誘導的熱痛覺過敏,並抑制SGCs數量的增加。
摘要(英) Rheumatoid arthritis (RA), a common autoimmune disease, is characterized by chronic inflammation of the synovial joints, leading to joint damage and long-term pain. Joint inflammation is often accompanied for tissue acidosis. The previous study has found that proton-sensing receptors, ASIC3, TRPV1 and TDAG8, reduce RA-induced mechanical hyperalgesia and arthritis scores. However, it remains unclear whether these genes also affect RA-induced thermal hyperalgesia and how they regulate RA-induced pain. Previous studies have shown that satellite glial cells (SGCs) are critical to the development and maintenance of chronic pain. It is likely that proton-sensing receptors may regulate SGCs to modulate pain. To address this question, I injected 5 μg of Freund′s Complete Adjuvant (CFA) into the joints every week for four weeks and performed behavioral tests and immunohistochemical staining. Repeated CFA resulted in long-term joint inflammation, bilateral thermal hyperalgesia, DRG neuron loss, and an increase in the number of SGCs. Interestingly, ASIC 3, TRPV 1 and TDAG 8 knockout mice reversed arthritis-induced thermal hyperalgesia from 7-9 weeks, and inhibited the increase in the number of SGCs.
關鍵字(中) ★ 類風濕性關節炎
★ 衛星膠細胞
關鍵字(英) ★ Rheumatoid arthritis
★ satellite glial cells
★ ASIC3
★ TRPV1
★ TDAG8
論文目次 中文摘要 I
ABSTRACT II
致謝 III
目錄 IV
圖表目錄 VII
表目錄 VIII
第一章 緒論 1
1.1 類風濕性關節炎(RHEUMATOID ARTHRITIS, RA) 2
1.2 神經膠質細胞(GLIAL CELLS) 3
1.2.1 衛星膠細胞(Satellite glial cells, SGCs)在關節炎中扮演的角色 3
1.3 酸敏感的受體和離子通道 4
1.3.1 酸敏感離子通道3(Acid-sensing ion channel, ASIC3) 4
1.3.2 辣椒素受體1(Transient receptor potential vanilloid channel 1, TRPV1) 5
1.3.3 T細胞死亡相關基因8(T cell death associated gene 8, TDAG8) 6
1.4 研究動機與目的 7
第二章 材料與方法 9
2.1 實驗材料 10
2.1.1 實驗動物 10
2.1.2 實驗藥品 10
2.2 實驗方法 11
2.2.1 小鼠基因型判定 (Genotyping) 11
2.2.2 瓊酯醣膠的製備與分析 13
2.2.3 小鼠關節炎模式及關節炎程度評估 13
2.2.4 機械性痛覺行為實驗 (Von-Frey filaments test) 14
2.2.5 熱痛覺行為實驗 (Hargreavs’ test) 14
2.2.6 組織冷凍切片的製作 15
2.2.6.1 玻片前處理 15
2.2.6.2 組織包埋及冷凍組織切片 15
2.2.6.3 免疫染色 (Immunohistochemistry) 16
2.2.7 統計分析 17
第三章 結果 18
3.1 重複注射完全弗氏佐劑(CFA)誘發長期關節炎與熱痛覺過敏現象 19
3.2 在野生型小鼠中長期性關節炎疼痛誘導DRG神經元數量的變化 20
3.3 在CFA誘導長期性關節炎小鼠後SGCS的表現 21
3.4 在基因ASIC3-/-小鼠關節連續注射CFA後減緩熱痛覺敏感現象 22
3.5 在基因ASIC3-/-小鼠關節連續注射CFA後減緩SGCS表現 23
3.6 在基因TRPV1-/-小鼠關節連續注射CFA後減緩熱痛覺敏感現象 24
3.7 在基因TRPV1-/-小鼠關節連續注射CFA後減緩SGCS表現 25
3.8 在基因TDAG8-/-小鼠關節連續注射CFA後減緩機械性和熱痛覺敏感現象 26
3.9 在基因TDAG8-/-小鼠關節連續注射CFA後減緩SGCS表現 27
第四章 結果與討論 29
4.1 模擬類風濕性關節炎的動物模式誘發熱痛覺過敏 30
4.2 在野生型小鼠中長期性關節炎疼痛誘導DRG神經元數量的減少 31
4.3 在野生型小鼠中誘導慢性關節炎疼痛後DRG中衛星膠質細胞的表現 32
4.4 ASIC3、TRPV1及TDAG8基因剔除會減緩關節腫脹和熱痛覺敏感現象 33
4.5 剔除ASIC3、TRPV1或TDAG8基因的關節炎小鼠會抑制衛星膠質細胞的表現 35
第五章 參考文獻 37
附錄 62
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指導教授 孫維欣(Wei-Hsin Sun) 審核日期 2019-6-27
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