博碩士論文 101224022 詳細資訊




以作者查詢圖書館館藏 以作者查詢臺灣博碩士 以作者查詢全國書目 勘誤回報 、線上人數:12 、訪客IP:35.172.233.215
姓名 黃郁雰(Yu-Fen Huang)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 剔除ASIC3或TRPV1基因會縮短經發炎產生的長期機械性痛覺敏感現象
(Deletion of ASIC3 or TRPV1 gene shortens chronic mechanical hyperalgesia induced by inflammation)
相關論文
★ 週邊發炎反應增加酸敏感受體- TDAG8基因在背根神經節之表現量★ 酸敏感G蛋白偶合受體,G2A,在ASIC3基因剔除小鼠中改變表現量
★ MrgB4受體專一表現於感覺神經元,且在ASIC3基因剔除小鼠中有不同的表現。★ 血清素受體2B對酸敏感離子通道3與辣椒素受體1的影響
★ 酸敏感G蛋白偶合受體在小鼠背根神經節神經元中的訊息傳導路徑★ 酸敏感G蛋白偶合受體功能上的拮抗機制
★ TDAG8活化後經由PKA與PKCε增強辣椒素受體的敏感度★ 台灣海岸植物之內生真菌多樣性研究
★ 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★ 抑制OGR1表現可減緩慢性神經性疼痛藉由減少顆粒性白血球數及非IB4神經元之鈣訊號
★ 抑制OGR1及G2A表現可藉由調控非IB4神經元鈣訊號減緩酸所誘導長期疼痛★ G-蛋白偶合接受體與G-蛋白訊號調控蛋白之整合型資料庫
★ 血清素受體2B基因在酸敏感受體3基因剔除小鼠的背根神經節中表現量增加★ 酸敏感的G蛋白偶合受體─OGR1表現在背根神經節內與痛覺相關的感覺神經元上
★ 血清素受體2B參與血清素引起的機械性痛覺過敏★ 血清素受體2B調控鈣離子變化影響機械性痛覺敏感
檔案 [Endnote RIS 格式]    [Bibtex 格式]    [相關文章]   [文章引用]   [完整記錄]   [館藏目錄]   [檢視]  [下載]
  1. 本電子論文使用權限為同意立即開放。
  2. 已達開放權限電子全文僅授權使用者為學術研究之目的,進行個人非營利性質之檢索、閱讀、列印。
  3. 請遵守中華民國著作權法之相關規定,切勿任意重製、散佈、改作、轉貼、播送,以免觸法。

摘要(中) 當組織受傷,受損細胞釋放出多種化學物質,如氫離子、前列腺素E2、生長因子、細胞因子、激肽等。這些發炎介質會透過活化蛋白質激酶A (PKA)或蛋白質激酶Cε (PKCε) 使痛覺相關的傷害感受器敏感,進而導致發炎性疼痛。並由之前的研究結果證實急性轉為慢性發炎性疼痛與PKA和PKCε有關。但目前還不清楚是由哪些基因參與調節。也由於氫離子在過去的實驗中有發現是誘發發炎性疼痛很重要的因素,因此認為酸敏感受體於PKA與PKCε轉換之間扮演著重要的角色。為了解決這個問題,我們使用基因剔除或過度表現酸敏感受體的小鼠進行實驗。結果發現無論ASIC3和TRPV1基因剔除小鼠都會縮短CFA引起的機械性痛覺敏感現象。此外,由TRPV1拮抗劑阻斷TRPV1基因也可縮短了CFA誘發的慢性機械性痛覺敏感現象。並於早期階段G2A的過度表現可以透過Gαi路徑降低由
CFA引起的機械性痛覺敏感現象。
摘要(英) When tissues are injured, damaged cells release multiple chemical mediators, such as protons, PGE2, growth factors, cytokines, kinins and so on. These inflammatory mediators activate protein kinase A (PKA) or protein kinase Cε (PKCε) to sensitize pain-related nociceptor afferents, leading to inflammatory pain. Previous studies have been demonstrated that the transition from acute to chronic inflammatory pain requires the switch of PKA and PKCε-dependency. However, it remains unclear which genes regulate the switch of kinase dependence. Since proton is the decisive factor to induce inflammatory pain, proton-sensing receptors could play an important role in the switch of PKA and PKCε dependency. To address this question, we generated knockout or overexpression mice for proton-sensing receptors. I found that both ASIC3 and TRPV1 knockout mice had shortened CFA-induced mechanical hyperalgesia. Moreover, blocking of TRPV1 by TRPV1 antagonist also shortened CFA-induced chronic mechanical hyperalgesia. Overexpression of G2A reduced CFA-induced mechanical hyperalgesia in early phase through Gαi pathway.
關鍵字(中) ★ 辣椒素受體
★ 酸敏性受體
★ 完全弗氏佐劑
關鍵字(英) ★ TRPV1
★ ASIC3
★ G2A
★ CFA
論文目次 目 錄
中文摘要 …………………………………………………………….…………………………... I
英文摘要 ……………………………………………………………………………..…………. II
致謝 ………………………………………………………………………………….………… III
目錄…………………………………………………………………………………………….. IV
圖目錄…………………………………………………………………………………………..VII
表目錄………………………………………………………………………………………….VIII
第一章 緒論 1
1.1 慢性疼痛 2
1.2發炎性疼痛 (Inflammatory pain) 3
1.3預發炎模式 (Hyperalgesic priming) 4
1.4離子通道 5
1.4.1 酸敏感離子通道 (Acid-sensing ion channel, ASICs) 5
1.4.2 辣椒素受體 (Transient receptor potential vanilloid channel 1, TRPV1) 6
1.4.3 酸敏感G蛋白偶合受體- OGR1家族 (Proton-sensing G-protein coupled receptor) 7
1.5研究動機 10
第二章 實驗材料與方法 11
2.1 實驗材料 12
2.1.1 實驗菌株 12
2.1.2 實驗細胞株 12
2.1.3 實驗動物 12
2.1.4 實驗藥物 12
2.2 實驗方法 13
2.2.1 基因剔除小鼠基因型之辨別 (Genotyping of knockout mice) 13
2.2.2 動物疼痛模式 14
2.2.3 質體於背根神經節表現模式 14
2.2.4 機械性痛覺行為實驗 15
2.2.5 腳掌腫脹程度測量及蘇木素-伊紅染色 (H&E染色) 15
2.2.6 胞內與DRG cAMP累積量分析 16
2.2.7 組織包埋及冷凍組織切片與固定 17
2.2.8 基因分析實驗 18
2.2.9 數據統計分析 19
第三章 結果 20
3.1 小鼠皮下注射CFA引發長期發炎性疼痛模式 21
3.2 於野生型小鼠引發發炎反應後,TRPV1與ASIC3基因表現量會持續增加 22
3.3 剔除ASIC3 基因會縮短機械性痛覺持續時間,但發炎情形更加劇烈 22
3.5 剔除TRPV1 基因會縮短機械性痛覺持續時間,但發炎情形並無差異 24
3.6 抑制 TRPV1可以降低野生型小鼠的發炎性疼痛 25
3.7 小鼠腳掌皮下過度表現G2A可以降低pH 5.0 的酸所引起的機械性痛覺敏感現象 26
3.8 小鼠周邊皮下過度表現G2A可以降低CFA所引起的早期機械性痛覺敏感現象 27
3.9 於背根神經節中,在CFA誘發發炎反應中過度表現G2A 27
3.10 於小鼠過度表現G2A會使cAMP累積量下降 28
3.11 小鼠腳掌皮下過度表現G2A可以降低CFA所引起的早期機械性痛覺敏感現象是由Gαi路徑所調控 29
3.12 小鼠周邊皮下過度表現G2A可以降低CFA所引起的早期機械性痛覺敏感現象可能是經由抑制Gαs的路徑而產生的 29
第四章 討論 31
第五章 參考文獻 38
附錄 71
參考文獻 Aley KO, Messing RO, Mochly-Rosen D, Levine JD. (2000) Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J Neurosci. 20(12): 4680-5.

Basbaum AI, Bautista DM, Scherrer G, Julius D. (2009) Cellular and molecular mechanisms of pain. Cell. 139(2):267-84.

Bolick DT, Whetzel AM, Skaflen M, Deem TL, Lee J, Hedrick CC. (2007) Absence of the G protein-coupled receptor G2A in mice promotes monocyte/endothelial interactions in aorta. Circ Res. 100(4):572-80.

Booden, M. A., Siderovski, D. P. and Der, C. J. (2002). Leukemia-associated Rho guanine nucleotide exchange factor promotes Gαq-coupled activation of RhoA. Mol. Cell. Biol. 22, 4053-4061.

Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen Zeitz KR, Koltzenberg M, Basbaum AI, Julius D. (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 288:306-313.

Chang CJ. (2014) The role of T-cell death – associated gene 8 in inflammatory pain.

Chen WN, Lee CH, Lin SH, Wong CW, Sun WH, Wood JN and Chen CC. (2014) Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. Mol Pain. 10: 40.

Chen YJ, Huang CW, Lin CS, Chang WH and Sun WH. (2009) Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain. Mol Pain. 5:39.

Costigan M., Scholz J., and Woolf C.J. (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32, 1–32.

da Costa DS, Meotti FC, Andrade EL, Leal PC, Motta EM, Calixto JB. (2010) The involvement of the transient receptor potential A1 (TRPA1) in the maintenance of mechanical and cold hyperalgesia in persistent inflammation. Pain. 148(3):431-7.

Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405:183–187.

Decaris, E., Guingamp, C., Chat, M., Philippe, L., Grillasca, J.P., Abid, A., Minn, A., Gillet, P., Netter, P. & Terlain, B. (1999) Evidence for neurogenic transmission inducing degenerative cartilage damage distant from local inflammation. Arthritis Rheum, 42, 1951–1960.

Deval E, Noel J, Lay N, alloui A, Diochot S, Friend V, Jodar M, Lazdunski M, Lingueglia E. (2002) ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J., 27:3047-3055.

Ferrari LF, Araldi D, Levine JD. (2015) Distinct terminal and cell body mechanisms in the nociceptor mediate hyperalgesic priming. J Neurosci. 35(15):6107-16.
Gao X1, Ding G, Wang Z, Fu H, Ni Z, Ma J, Song S, Liu F, Fu Z. (2010) Adjuvant treatment suppresses IL-17 production by T cell-independent myeloid sources in nonobese diabetic mice. Mol Immunol. 47(14):2397-404.

Gaskin DJ and Richard P. (2012) The economic costs of pain in the United States. J Pain. 13, 715-724.

Gatchel RJ, McGeary DD, McGeary CA and Lippe B. (2014) Interdisciplinary chronic pain management: past, present, and future. Am Psychol. 69(2):119-30.

Honore P, Wismer CT, Mikusa J, Zhu CZ, Zhong C, Gauvin DM, Gomtsyan A, El Kouhen R, Lee CH, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF. (2005) A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats. J Pharmacol Exp Ther 314: 410–421.

Huang J, Zhang X, McNaughton PA. (2006) Inflammatory pain: the cellular basis of heat hyperalgesia. Curr Neuropharmacol. 4(3):197-206.

Huang WY, Dai SP, Chang YC, Sun WH. (2015) Acidosis mediates the switching of Gs –PKA and Gi -PKCε dependence in prolonged hyperalgesia induced by inflammation. PLOS ONE, 10 (5).

Huang CW, Tzeng JN, Chen YJ, Tsai WF, Chen CC, Sun WH. (2007) Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors. Mol Cell Neurosci. 36(2):195-210.

Julius D and Basbaum AI. (2001) Molecular mechanisms of nociception. Nature, 413:203-10.

Jiehong Huang, Xuming Zhang and Peter A. McNaughton.(2006) Inflammatory Pain: The Cellular Basis of Heat Hyperalgesia. Current Neuropharmacology. 4, 197-206

Kabarowski JH, Zhu K, Le LQ, Witte ON, Xu Y. (2001) Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A. Science. 293(5530):702-5.

Kay H. Steen, Peter W. Reeh. (1992) Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin. Pain.66,163-170.

Lingueglia E (2007). Acid-sensing ion channels in sensory perception. J Biol Chem282: 17325–17329.
Ludwig M, Vanek M, Guerini D, Gasser JA, Jones CE, Junker U, Hofstetter H, Wolf RM, Seuwen K. (2003) Proton-sensing G-protein-coupled receptors. Nature, 425:93-98.

Murakami N, Yokomizo T, Okuno T, Shimizu T. (2004) G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine. J Biol Chem. 279(41):42484-91.

McCudden CR, Hains MD, Kimple RJ, Siderovski DP, Willard FS (2005) G-protein signaling: back to the future. Cell Mol Life Sci 62: 551–577

Molliver DC, Immke DC, Fierro L, Paré M, Rice FL, McCleskey EW. (2005) ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons. Mol Pain. 23;1:35.

Obinata H, Hattori T, Nakane S, Tatei K, Izumi T. (2005) Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A. J Biol Chem. 280(49):40676-83.

Peter W. Reeh and Kay H. Steen. (1996) Tissue acidosis in nociception and pain. Progress in Brain Research. 113:143-151

Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON. (2005) Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells. Proc Natl Acad Sci U S A. 102(5):1632-7.

Reeh PW and Steen KH. (1996) Tissue acidosis in nociception and pain. Prog Brain Res., 113:143-151.

Ren K, Dubner R. (2010) Interactions between the immune and nervous systems in pain. Nat Med. 16(11):1267-76.

Scholz J and Woolf CJ. (2002) Can we conquer pain? Nature Neurosci, 5(Suppl):1062-1067.

Schwartz ES, La JH, Scheff NN, Davis BM, Albers KM, Gebhart GF. (2013) TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis. J Neurosci. 33(13):5603-11.

Sluka KA, Kalra A, Moore SA. (2001) Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle Nerve. 24(1):37-46.

Sluka KA, Radhakrishnan R, Benson CJ., Eshcol JO., Price MP., Babinski K, Audette KM., Yeomans DC., Wilson SP. (2007) ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain. 129(1-2): 102–112.

Sluka KA, Rasmussen LA, Edgar MM, O′Donnell JM, Walder RY, Kolker SJ, Boyle DL, Firestein GS. (2013) Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis. Arthritis Rheum. 65(5):1194-202.

Steen KH, Reeh PW, Anton F, Handwerker HO (1992) Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro. J Neurosci 12: 86–95.

Steen KH, Issberner U, Reeh PW. (1995) Pain due to experimental acidosis in human skin: evidence for non-adapting nociceptor excitation. Neurosci Lett. 199(1):29-32.

Sutherland SP1, Benson CJ, Adelman JP, McCleskey EW. (2001) Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc Natl Acad Sci U S A. 98(2):711-6.

Tsia. (2007) Expression change of proton-sensing G-protein coupled receptor, G2A, in ASIC3 knockout mice.

Walker KM, Urban L, Medhurst SJ, Patel S, Panesar M, Fox AJ, McIntyre P. (2003) The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J Pharmacol Exp Ther. 304(1):56-62.

Weng Z, Fluckiger AC, Nisitani S, Wahl MI, Le LQ, Hunter CA, Fernal AA, Le Beau MM, Witte ON. (1998) A DNA damage and stress inducible G protein-coupled receptor blocks cells in G2/M. Proc Natl Acad Sci U S A. 95(21):12334-9.

Witte ON, Kabarowski JH, Xu Y, Le LQ, Zhu K. (2005) Retraction. Science. 307(5707):206.

Yen YT, Tu PH, Chen CJ, Lin YW, Hsieh ST and Chen CC. (2009) Role of acid-sensing ion channel 3 in sub-acute-phase inflammation. Mol Pain. 5:1.
指導教授 孫維欣(Wei-Hsin Sun) 審核日期 2015-6-23
推文 facebook   plurk   twitter   funp   google   live   udn   HD   myshare   reddit   netvibes   friend   youpush   delicious   baidu   
網路書籤 Google bookmarks   del.icio.us   hemidemi   myshare   

若有論文相關問題,請聯絡國立中央大學圖書館推廣服務組 TEL:(03)422-7151轉57407,或E-mail聯絡  - 隱私權政策聲明