酸敏感G蛋白偶合受體OGR1, G2A, GPR4經由不同方式調控發炎所產生的機械性痛覺敏感現象

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黃真(Jen Wong) 查詢紙本館藏

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論文名稱

酸敏感G蛋白偶合受體OGR1, G2A, GPR4經由不同方式調控發炎所產生的機械性痛覺敏感現象
(OGR1, G2A, and GPR4 regulate mechanical hyperalgesia induced by inflammation via distinct ways)

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摘要(中)

長期發炎性疼痛主要是發炎反應產生時會釋放發炎相關介質，其會活化或調控傷害感受器，導致疼痛和痛覺敏感的現象產生。發炎介質中的酸會造成組織酸化，其為引發疼痛的重要因素。有二類酸敏性受體，一是酸敏感性離子通道，另一個則是酸敏感性G蛋白耦合受體。酸敏感性G蛋白耦合受體，包含OGR1、 GPR4、 G2A和TDAG8，可以表現在小直徑的痛覺神經中。TDAG8在注射CFA後1天表現量會增加，而G2A則是在90分鐘時增多。將TDAG8基因表現量降低可以延遲CFA所誘導的痛覺敏感現象，而過度表現G2A則可以降低CFA所引起的早期的痛覺敏感現象。這些研究指出TDAG8可能有促進疼痛的角色，而G2A則是有抑制疼痛的角色。然而，目前其它酸敏感性G蛋白耦合受體在發炎性疼痛中所扮演的角色仍然不清楚。為了解決這個問題，我的實驗中使用short-hairpin RNA (shRNA)來抑制酸敏感性G蛋白耦合受體的基因，探討他們在疼痛上的角色。我發現抑制OGR1會在CFA注射後4小時減緩機械性痛覺敏感現象，並且減少粒細胞的數量。而抑制G2A除延長機械性痛覺敏感現象外，另會在42天增加粒細胞的數量。抑制GPR4雖會延長痛覺敏感現象，但並不會改變免疫細胞數量的變化。

摘要(英)

Chronic inflammatory pain results from inflammation that releases the mediators to activate or modulate the nociceptors, leading to pain and hyperalgesia. Tissue acidosis appears to be a dominant factor in inflammatory pain, and the acidosis signals can be sensed by the proton-sensing ion channels and G proton-coupled receptors (GPCRs). The proton-sensing GPCRs, Ovarian cancer G protein-coupled receptor 1 (OGR1), G protein-coupled receptor 4 (GPR4), G2 accumulation (G2A), and T-cell death associated gene 8 (TDAG8), were found in small-diameter nociceptors, and TDAG8 expression was increased at 1 day, while G2A expression increased at 90 minutes after CFA inflammation. The inhibition of TDAG8 delays the onset of CFA-induced hyperalgesia, whereas overexpression of G2A reduced hyperalgesia at the early phase. These results suggested that TDAG8 may have a pro-nociceptive role, and G2A have an anti-nociceptive role in CFA-induced hyperalgesia. However, the roles of other proton-sensing GPCRs in inflammatory pain are still unclear. To address this issue, proton-sensing GPCRs were knocked down with short hairpin RNA. I have found that OGR1 knockdown mice significantly reduced mechanical hyperalgesia and decreased the number of granulocytes at 4 hours after CFA injection. Moreover, knockdown of G2A prolonged mechanical hyperalgesia and increased the number of granulocytes at 42 days, whereas GPR4 knockdown mice prolonged hyperalgesia but did not change the number of immune cells.

關鍵字(中)

★ 酸敏感性G蛋白耦合受體
★ 完全弗氏佐劑

關鍵字(英)

★ OGR1
★ G2A
★ GPR4
★ CFA

論文目次

中文摘要i
Abstract ii
Acknowledgements iii
Table of Contents iv
List of Figures vii
List of Tables viii

Table of Contents
Chapter 1 Introduction 1
1.1. Pain 2
1.2 Inflammatory pain 3
1.3 Tissue Acidosis 5
1.4 Proton-sensing receptors 5
1.4.1 Proton-sensing G protein-coupled Receptors 6
1.4.1.1 Ovarian cancer G protein-coupled receptor 1 (OGR1) 6
1.4.1.2 G2 accumulation (G2A) 7
1.4.1.3 G protein-coupled receptor 4 (GPR4) 8
1.4.1.4 T cell death-associated gene 8 (TDAG8) 9
1.5 Research purpose 10
Chapter 2 Materials and methods 11
2.1 Materials 12
2.1.1 Experimental bacterial strains and animals 12
2.1.2 Agents and Chemicals 12
2.1.3 Plasmids (RNA interference) 13
2.2 Methods 13
2.2.1 Amplification and purification of plasmid 13
2.2.1.1 Bacterial transformation 13
2.2.1.2 Mini preparation 13
2.2.1.3 Midi preparation 14
2.2.2 Subcloning of shRNA 15
2.2.2.1 Preparation of vectors 15
2.2.2.2 Preparation of inserts 15
2.2.2.3 Preparation of inserts 16
2.2.3 Animal experiments 16
2.2.3.1 Inflammatory pain model 16
2.2.3.2 Behavioral tests 16
2.2.4 Immunohistochemistry 17
2.2.4.1 Slides preparation 17
2.2.4.2 Tissue collection and sectioning 17
2.2.4.3 Immunostaining 17
2.2.5 Hematoxylin and Eosin staining 18
2.2.6 Data analysis 19
Chapter 3 Results 20
3.1 Cloning map of shTDAG8-B1, shOGR1-26108, shG2A-27458, shG2A-27477, and shGPR4-28164 21
3.2 Intraplantar injection of CFA induces long-term mechanical hyperalgesia in ICR and C57BL/6 mice 21
3.3 Intraplantar injection of CFA induces mechanical hyperalgesia and inflammation in cherry vector-treated mice 22
3.4 Knockdown of OGR1 can reduce CFA-induced mechanical hyperalgesia and decreases granulocytes at 4 hours 23
3.5 Knockdown with shG2A-27477 prolongs CFA-induced inflammatory pain and increases granulocytes at day 42, and knockdown with shG2A-27458 is not effective in CFA inflammatory pain and inflammation 24
3.6 Knockdown of GPR4 prolongs CFA-induced mechanical hyperalgesia but does not enhance inflammation at day 42 27
3.7 Knockdown and knockout of TDAG8 reduces pain CFA-induced mechanical hyperalgesia 28
Chapter 4 Discussion 30
4.1 Long-term mechanical hyperalgesia induced by CFA 31
4.2 Changes in immune cell numbers during inflammatory pain 32
4.3 Inhibition of OGR1 reduces CFA-induced mechanical hyperalgesia and decreases number of granulocytes at 4 hours 32
4.4 Knockdown with shG2A-27477 prolongs CFA-induced mechanical hyperalgesia, and knockdown with shG2A-27458 is not effective in inflammatory pain 33
4.5 Inhibition of GPR4 prolongs CFA-induced hyperalgesia but doesn’t enhance inflammation 35
4.6 Inhibition of TDAG8 reduces hyperalgesia and shortens inflammatory hyperalgesia 36
4.7 Conclusion 37
Chapter 5 References 38
Appendix 65

List of Figures
Figure 3.1 The maps of shRNA constructs 46
Figure 3.2 CFA injection induces mechanical hyperalgesia in ICR and C57BL/6 wild-type mice 47
Figure 3.3 CFA injection induces mechanical hyperalgesia in vector-injected mice 48
Figure 3.4 CFA injection induces immune cell infiltration in vector-injected mice 49
Figure 3.5 Knockdown of OGR1 reduces CFA-induced inflammatory pain at 240 minutes 50
Figure 3.6 Knockdown of OGR1 decreases number of granulocytes at 4 hours after CFA injection 51
Figure 3.7 Knockdown with shG2A-27477 prolongs mechanical hyperalgesia, while knockdown with shG2A-27458 does not affect mechanical hyperalgesia 53
Figure 3.8 Knockdown with shG2A-27477 enhances inflammation at 42 days 54
Figure 3.9 Knockdown with shG2A-27458 does not change the number of immune cells at 28 days 55
Figure 3.10 Knockdown of GPR4 prolongs CFA-induced mechanical hyperalgesia 56
Figure 3.11 Knockdown of GPR4 does not change the number of immune cells at 42 days 57
Figure 3.12 Knockdown and knockout of TDAG8 significantly reduces CFA-induced inflammatory pain 58

List of Tables
Table 2.1 Information of shRNA plasmids 59
Table 3.1 The number of immune cells in vector-injected paws 60
Table 3.2 The number of immune cells in shOGR1-26108-injected paws 61
Table 3.3 The number of immune cells in shG2A-27477-injected paws 62
Table 3.4 The number of immune cells in shG2A-27458-injected paws 63
Table 3.5 The number of immune cells in shGPR4-28164-injected paws 64

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指導教授

孫維欣(Wei-Hsin Sun)

審核日期

2017-10-6

推文