博碩士論文 105821025 詳細資訊




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姓名 李家維(Chia-Wei Lee)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 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
(Knockdown of both OGR1 and G2A relieves acid-induced pain by modulating calcium signals in IB4-negative neurons)
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摘要(中) 在各種病變和損傷中發現高局部濃度的氫離子,例如纖維肌痛,免疫疾病或關節炎,是慢性疼痛的一部分。組織酸中毒引發信號轉換(酸注射後2-4小時)從Gs-蛋白激酶A(PKA)到Gi-蛋白激酶Cε(PKCε),PKA-PKCε信號開關與痛覺過敏引發的發展相關。酸敏感G蛋白偶聯受體,包括OGR1,G2A,TDAG8和GPR4,可能是介導PKA-PKCε信號轉換的主要候選者。我們以前發現T細胞死亡相關基因8(TDAG8)介導酸中毒信號並與Gs蛋白偶聯以激活PKA途徑,引發痛覺過敏。 TDAG8-Gs-PKA途徑也參與痛覺過敏的引發。然而,PKA-PKCε信號轉換的潛在機制仍不清楚。在這項研究中,我們使用shRNA技術來探索從急性疼痛到慢性疼痛的轉變。在二次注射酸模型中(酸[pH5.0]注射兩次,間隔5天),給予G2A-和OGR1-shRNA質粒顯著抑制第一次痛覺過敏的延長期(4小時後)並縮短其持續時間。第二次痛覺過敏對應於Gi-PKCε信號傳導的作用時間。鑑於G2A和OGR1的異聚體介導Gi信號傳導,G2A和OGR1可通過調節Gi-PKCε信號傳導參與痛覺過敏引發的建立。
摘要(英) High local concentration of protons was found in kinds of lesions and injury, such as fibromyalgia, immune disease or arthritis, accounted for part of chronic pain. Tissue acidosis triggers a signal switch (2-4hr after acid injection) from Gs-protein kinase A (PKA) to Gi-protein kinase Cε (PKCε) and the PKA-to-PKCε signal switch is associated with development of hyperalgesic priming. Proton-sensing G-protein-coupled receptors including OGR1, G2A, TDAG8, and GPR4, could be major candidates to mediate the PKA-to-PKCε signal switch. We have previously found that T-cell death-associated gene 8 (TDAG8) mediates acidosis signals and couples to Gs protein to activate PKA pathway, initiating hyperalgesia. TDAG8-Gs-PKA pathway also participates in the establishment of hyperalgesic priming. However, the mechanism underlying the PKA-to-PKCε signal switch remains unclear. In this study, we used shRNA knockdown technique to explore the transition from acute to chronic pain. In the dual acid injection model (acid [pH5.0] injected twice, 5 days apart), administration of both G2A- and OGR1-shRNA plasmids significantly inhibited the prolonged phase (after 4hr) of the first hyperalgesia and shortened the duration of the second hyperalgesia, which corresponds to the action time of the Gi-PKCε signaling. Given that a heteromer of G2A and OGR1 mediates Gi-signaling, G2A and OGR1 may participate in the establishment of hyperalgesic priming through regulation of the Gi-PKCε signaling.
關鍵字(中) ★ 疼痛
★ 痛覺過敏感
★ 長期疼痛
關鍵字(英) ★ hyperalgesia
★ pain
★ OGR1
★ G2A
★ hyperalgesic priming
論文目次 Abstract…………………………………………………………………………………………i
Acknowledgement……………………………………………………………………………..ii
Table of Contents………………………… …………………………………………………..iii
List of Figures……………………………………………………………………......……….vii
List of Tables……………………………………………………………………………...…...iv

Table of Contents
Chapter 1 Introduction…………………………………………………….…..1
1.1 Pain and nociception……………………………………………………………………….2
1.1.1 Nociceptor………………………………………………………………………………..3
1.1.2 Pathways of nociception…………………………………………………………………3
1.2 Pain associated with tissue acidosis………………………………………………………..3
1.3 Hyperalgesic priming………………………………………………………………………4
1.3.1 Repeated-inflammatory mediator injection induced hyperalgesic priming……………...4
1.3.2 Repeated-acid injection induced hyperalgesic priming………………………………….5
1.4 Proton-sensing receptors…………………………………………………………………...6
1.4.1 Proton-sensing ion channels……………………………………………………………...6
1.4.1.1 Transient receptor potential vanilloid 1 (TRPV1)……………………………………...6
1.4.1.2 Acid-sensing ion channels 3 (ASIC3)………………………………………………….6
1.4.2 Proton-sensing G protein-coupled receptors (GPCRs)…………………………………7
1.4.2.1 Ovarian cancer G protein-coupled receptor 1 (OGR1)……………………………….7
1.4.2.2 T cell death-associated gene 8 (TDAG8)………………………………………………7
1.4.2.3 G2 accumulation protein (G2A)………………………………………………………8
1.5 Research propose………………………………………………………………………….8

Chapter 2 Materials and methods……………………………………………..9
2.1 Materials……………………………………………..……………………………………10
2.1.1 Experimental animals……………………………...……………………………………10
2.1.2 Cell lines…………………………………………………..……………………………10
2.1.3 RNA interference………………………………….……………………………………10
2.1.4 Plasmids………………………………………………...………………………………10
2.1.5 Agents and Chemicals……………………………..……………………………………11
2.1.6 Experimental tools………………………………………………………………………11
2.2 Experimental methods……………………………………….……………………………11
2.2.1 Amplification and purification of plasmids………………………..……………………11
2.2.1.1 Bacteria transformation………………………………………………….……………11
2.2.1.2 Overnight culture and strain preservation…………………….………………………12
2.2.1.3 Mini preparation………………………………………………….…………………..12
2.2.1.4 Agarose gel electrophoresis………………………………………………….……….12
2.2.1.5 Midi preparation………………………………………………….…………………..13
2.2.2 Subcloning of shRNA……………………………………………….………………….14
2.2.2.1 Preparation of vector………………………...…………………….………………….14
2.2.2.2 Preparation of inserts…………………………..………………….………………….14
2.2.2.3 Plasmid ligation…………………………..……………..…….………..…………….15
2.2.3 Cell line calcium imaging assay………………….………..………..………….………15
2.2.3.1 Cell subculture…………………………..………………………….……………….15
2.2.3.2 Preparation of coating cover slips………………………………………………….…15
2.2.3.3 Transfection…………………………..………………….……….…….…………….16
2.2.3.4 Calcium imaging………………………..……………………..……….…………….16
2.2.5 Analysis of animal gene expression…………………………..………..…………….…17
2.2.5.1 Tissue collection…………………………..………………..……..………………….17
2.2.5.2 RNA extraction and cDNA synthesis……………………………..………………….17
2.2.5.3 Real-time quantitative PCR (QPCR) …………………………….………………….19
2.2.6 Animal experiments…………………………..…………………….………………….19
2.2.6.1 Genotyping…………………………..…………………………...………………….19
2.2.6.2 Dual-acid model…………………………..……………….…….………………….20
2.2.6.3 shRNA knockdown…………………………..……………...…….………………….20
2.2.6.4 Animal behavioral test (Von Frey filaments) ……………….…….………………….21
2.2.7 Primary culture cell calcium imaging assay………………….…….………………….21
2.2.7.1 Preparation of coating cover slips…………………………….….………………….21
2.2.7.2 Primary culture…………………………..………………….……….……………….21
2.2.7.3 Calcium imaging………………………..……………………….….……………….23
2.2.8 Hematoxylin and Eosin staining……………..………….…….…….………………….23
2.3 Statistics…………………………..………………….…….…………………...……….24

Chapter 3 Results……………………………………………………………..25
3.1 Cloning maps of shG2A-27458, shG2A-27477, shOGR1-26080, shOGR1-26106, shOGR1-26108 and delivery of plasmid/catioized gelatin (CG) complexes…………………26
3.2 Knockdown of OGR1 reduces acid-induced calcium signals in vitro………………………26
3.3 Knockdown with shG2A and shOGR1 reduces the expression of target gene in vivo……27
3.4 Knockdown of G2A and OGR1 relieves acid-induced mechanical hyperalgesia………..27
3.5 Inhibition of PKA reduces the first 2 hours acid-induced hyperalgesia; inhibition of PKCε, Giα, and Giβ/γ reverses acid-induced hyperalgesia……………………………………………28
3.6 Knockdown of G2A and OGR1 does not affect the number of immune cells after 4 hours of acid injection…………………………………..………………….………………………..28
3.7 Knockdown of G2A and OGR1 changes calcium signals in IB4-negative neurons at 4 hours after acid injection…………………………..………………….………………………29
3.8 ASIC3 plays major role on acid-induced hyperalgesia after 6 hour of acid injection……29
3.9 Intraplantar injection of pH5.0 acid induces nociceptors in primed state at 4 to 9 days after acid injection…………………………..………………….…………………………………..30
3.10 G2A, OGR1, and ASIC3 participate in BTB09089-induced mechanical hyperalgesia…30

Chapter 4 Discussion…………………………………………………………31
4.1 The efficiency of shRNA knockdown…………………….…..…………………………32
4.2 Knockdown with shG2A-27458 and shOGR1-26108 reversed acid-induced hyperalgesia at 3 hours after acid injection……………………………….………………………………..32
4.3 Knockdown of G2A and OGR1 relieves acid-induced hyperalgesia by neuroplasticity...33
4.4 Knockdown of G2A and OGR1 changes the patterns of calcium influx induced by pH6.8 stimuli at 4 hours after injection……………………………………………………….…….33
4.5 Knockout of ASIC3 reversed acid-induced hyperalgesia at 6 hours after acid injection..34
4.6 Conclusion……………………………………………………………………………….34

Chapter 5 References…………………………………………………………36
Appendix………………………………………………………………………………….…..76







List of Figures
Figure 3.1 The maps of shRNA plasmid construct and delivery of plasmid/cationized gelatin (CG) complexes………………………………………………………………………………42
Figure 3.2 OGR1 knockdown attenuates acid-induced intracellular Ca2+ influx in transfected HEK293T cells………………………………………………………………………………..44
Figure 3.3 The gene expression level of proton-sensing GPCRs after shRNA treatment……46
Figure 3.4 Inhibition of G2A or OGR1 shortens the second acid-induced hyperalgesia……..48
Figure 3.5 Inhibition of G2A and OGR1 shortens the second acid-induced hyperalgesia…...49
Figure 3.6 Inhibition of PKA, PKCε, Giα, and Giβ/γ relieves acid-induced hyperalgesia…….50
Figure 3.7 Granulocytes increases in vector group at 4 hours after acid injection……...……51
Figure 3.8 Knockdown of both G2A and OGR1 does not affect the number of immune cells after 4 hours of acid injection……………………...…………………………………………52
Figure 3.9 Injection of pH5.0 acid does not change the highest peak of DRG neurons responding induced by pH6.8 stimuli at 4 hours after injection………….………………….54
Figure 3.10 Injection of pH5.0 acid changes the patterns of DRG neurons responding induced by pH6.8 stimuli at 4 hours after injection…………………………………………………..56
Figure 3.11 Knockdown of G2A and shOGR1 changes the amplitude of calcium influx in IB4-negative neurons induced by pH6.8 stimuli…………………………………………….57
Figure 3.12 Knockdown of G2A and OGR1 changes the patterns of DRG neurons responding induced by pH6.8 stimuli at 4 hours after injection…………………………………………59
Figure 3.13 ASIC3-/- mice did not establish mechanical hyperalgesia over 7hr……………60
Figure 3.14 Duration time of acid injection model…………………...……………………...61
Figure 3.15 Inhibition of G2A and OGR1 by co-transfected shG2A and shOGR1 can shorten the dual-TDAG8 agonist induced hyperalgesia………………………………………………62
Figure 3.16 Inhibition of PKCε and Giα relieves TDAG8 agonist-induced hyperalgesia……63
Figure 3.17 Mechanism of acid-induced hyperalgesia……………………………………..64




List of Tables
Table 3.1 The information of shRNA plasmids………………………………………………65
Table 3.2 The gene expression level of proton-sensing receptors at baseline (Wild-type mice)………………………………………………………………………………………….66
Table 3.3 The gene expression level of proton-sensing receptors by injecting cherry vector 12.5μg/mice at baseline………………………………………………………………………67
Table 3.4 The gene expression level of proton-sensing receptors by injecting cherry-shG2A-27477 12.5μg/mice at baseline………………………………………………68
Table 3.5 The gene expression level of proton-sensing receptors by injecting cherry-shG2A-27458 12.5μg/mice at baseline……………………………………………….69
Table 3.6 The gene expression level of proton-sensing receptors by injecting cherry-shOGR1-26108 12.5μg/mice at baseline……………………………………………..70
Table 3.7 The gene expression level of proton-sensing receptors by injecting cherry-shOGR1-26108 + cherry-shG2A-27458 6.25 + 6.25μg/mice at baseline…………….71
Table 3.8 The number of pH6.8 responding DRG neurons at baseline in cherry vector-treated mice…………………………………………………………………………………………..72
Table 3.9 The number of pH6.8 responding DRG neurons at 4 hours after pH5.0 acid injection in cherry vector-treated mice…………………………………………………………………73
Table 3.10 The number of pH6.8 responding DRG neurons at baseline in shG2A and shOGR1 co-treated mice……………………………………………………………………………….74
Table 3.11 The number of pH6.8 responding DRG neurons at 4 hours after pH5.0 acid injection in shG2A and shOGR1 co-treated mice…………………………………………….75
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指導教授 孫維欣(Wei-Hsin Sun) 審核日期 2019-8-26
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