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研究生：	薛建民 Hsueh, Chien-Min
論文名稱：	周邊注射脂多醣於腫瘤壞死因子受體Ⅱ基因剃除鼠所引起不同腦區微膠細胞活化之探討 Activation of microglia in the brain regions of tumor necrosis factor receptor-II knockout mice after intraperitoneal injection with lipopolysaccharide
指導教授：	曾淑芬 Tzeng, Shun-Fen
學位類別：	碩士 Master
系所名稱：	生物科學與科技學院 - 生命科學系 Department of Life Sciences
論文出版年：	2011
畢業學年度：	99
語文別：	英文
論文頁數：	75
中文關鍵詞：	腫瘤壞死因子受體2 、脂多醣、周邊發炎、微膠細胞
外文關鍵詞：	TNFR2, lipopolysaccharide, peripheral inflammation, microglia
相關次數：	點閱：91 下載：1
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已知周邊發炎能夠透過活化中樞神經中的微膠細胞，進一步引起中樞神經系統的免疫反應。微膠細胞為中樞神經最重要的免疫細胞，一但活化後具有產生許多發炎因子的能力，因此微膠細胞被認為是引起中樞神經系統發炎的主要角色。此外，微膠細胞受到周邊的發炎反應的活化後所產生的發炎因子，也被認為是造成許多神經退化性疾病的主因。而微膠細胞的活化已知是透過中樞神經系統中的腫瘤壞死因子α(TNFα)所引起的，但TNFα具有兩種受體，分別是腫瘤壞死因子受體1(TNFR1)和腫瘤壞死因子受體2(TNFR2)，目前大多數的研究都著重在TNFR1而非TNFR2。因此，本實驗將探討TNFR2在周邊發炎反應所引起微膠細胞的活化過程中，扮演著何種角色。首先在第一部分先以BALB/c小鼠建立實驗動物模式，在連續注射酯多醣(LPS)七天所引起的周邊發炎反應過程中，只有在第一天發現小鼠產生熱痛覺過敏的現象，而體重的下降則出現在第二天。將腦部切片後進行免疫組織染色，發現在多個區域均有Iba1+微膠細胞的增生並呈現類似活化的樣貌。此外，各個腦區中只有TNFR2的mRNA表現量會上升。接著在第二部分則利用TNFR2基因缺失的老鼠做為實驗動物模式以釐清TNFR2所扮演的角色。經過連續注射LPS的對照組中，各個腦區也發現TNFR2的mRNA表現量會上升。在經過周邊LPS注射的TNFR2基因剔除鼠身上，發現其痛覺過敏反應持續的時間延長，而其微膠細胞的外型相較於對照組，呈現接近較活化的外型，此外，其CD11b的表現也較對照組來得多。透過這些觀察，我們推論在缺乏TNFR2的狀況下，周邊LPS的刺激下似乎會增加微膠細胞的免疫反應。最後，進一步發現缺乏TNFR2的情況之下容易造成神經膠質瘤的生長，並推測此現象可能和TNFR2缺失所造成免疫反應的增加有關。

It has been known that peripheral inflammation could induce the immune response of central nervous system (CNS). The main cause of neuroinflammation is resulted from the microglia activation. As the major immune cells in the CNS, microglia have the capacity to produce inflammatory cytokines once they are activated. Those inflammatory cytokines produced by microglia also have been implicated in many neurodegeneration diseases. The activation of microglia induced by peripheral inflammation is TNFα signaling dependent. There are two receptors for TNFα which are TNFR1 and TNFR2. Most of the studies focus on the effect of TNFR1 instead of TNFR2. In this study, in vivo studies were performed to investigate the role of TNFR2 in the microglia activation during peripheral inflammation induced by repeated LPS injection for seven days. In the first part of this study, we choose BALB/c mice as our animal model. BALB/c mice showed that reduction of body weight only occurs at Day 2 after LPS injection, whereas hyperalgesia occurs at Day 1. After seven injections of LPS, the number of Iba1+ microglia increased with the activated-like morphology in different regions of brain. Moreover, only the expression of TNFR2 mRNA increased in the different regions of brain. At the second part of study, we tried to clarify the role of TNFR2 in the microglia activation during peripheral inflammation by using TNFR2-/- mice. TNFR2 mRNA also increased in the different brain regions of control group with the LPS treatment. In the LPS-treated TNFR2-/- mice, the reaction of hyperalgesia was prolonged, and the morphology of Iba1+ microglia became more activated when compared to LPS-treated control group. Besides, the activation marker for microglia, CD11b, also increased in the LPS-treated TNFR2-/- mice relative to LPS-treated control group. Moreover, the growth of glioma in the TNFR2-/- mice also increased. According to these results, we concluded that TNFR2 defficiency may result in the hyper-activation of microglia inresponse to peripheral LPS treatment and also promote the growth of glioma.

摘要................................................1
ABSTRACT................................................2
ACKNOWLEDGEMENT.........................................4
CONTENT................................................5
LIST of FIGURES..................................7
ABBREVIATIONS...........................................10
INTRODUCTION..............................................11
MATERIALS and METHODS................................21
1.	Animals...............................21
2.	Genotyping.........................21
3.	Administration of lipopolysaccharide.............22
4.	Hot plate test for hyperalgesia analysis..........22
5.	Animal perfusion abd tissue preparation....23
6.	Immunohistochemistry (IHC)..........23
7.	Cell counting.............24
8.	RNA isolation...................24
9.	Reverse transcription and polymerase chain reaction (RT-PCR)..................25
10.	Real-Time Quantitative Polymerase Chain Reaction (Q-PCR) (Fang et al., 2011).......................26
11.	C6 Glioma Implantation (Fang et al., 2011).....26
RESULTS.............28
Part I: Effects of repeated peripheral LPS injection on micrglia activation in BALB/c mice..............28
Part II: Effect of repeated peripheral LPS injection on microglia activation in TNFR2 KO mice.........31
DISCUSSION.................................36
REFERENCES............................41
Figure 1. Effect of repeated LPS injection for seven days on anorexia-induced weight loss on BALB/c mice..........50
Figure 2. Effect of reapeted LPS injection for seven days on hot plate latencies on BALB/c mice..........51
Figure 3. An increase in Iba1+ microglia after repeated peripheral administration of LPS for seven days in BALB/c mice..................52
Figure 4. Microglia in hippocampus became more hypertrophy after repeated peripheral administration of LPS for seven days in BALB/c........................53
Figure 5. Microglia in the cerebellum increased after repeated peripheral administration of LPS for seven days in BALB/c........................................54
Figure 6. Microglia in brainstem showed hypertrophy after repeated peripheral administration of LPS for seven days in BALB/c..............................55
Figure 7. Expressions of TNFR2 mRNA analyzed by Q-PCR in the CNS of BALB/c mice.........................56
Figure 8. Expressions of TNFR2 mRNA analyzed by Q-PCR in the CNS of BALB/c mice.........................57
Figure 9. Genotyping and Q-PCR for TNFR1 mRNA expression in CNS of TNFR2+/- and TNFR2-/- mice...............58
Figure 10. Only TNFR2+/- mice express TNFR2 mRNA and the level also increased after LPS treatment.........59
Figure 11. Analysis of the effect on anorexia-induced weight loss in TNFR2+/- and -/- mice after daily LPS injection for seven days........................60
Figure 12. Measurement of thermal threshold of TNFR2+/- and TNFR2-/- mice receiving daily injection of LPS...........61
Figure 13. Significantly increased number of Iba1+ microglia cells after repeated peripheral administration of LPS for seven days in TNFR2+/- and TNFR2-/- mice......62
Figure 14. Morphological change of Iba1+ microglia cells after repeated peripheral administration of LPS for seven days was seen in cortex and hippocampus of TNFR2+/- mice...64
Figure 15. Significantly morphological change of Iba1+ microglia cells after repeated peripheral administration of LPS for seven days was observed in corpus callosum and cerebellum of TNFR2+/- mice.....................65
Figure 16. Significantly morphological change of Iba1+ microglia cells after repeated peripheral administration of LPS for seven days was observed in brainstem and area postrema of TNFR2+/- mice.....................66
Figure 17. Distribution of Iba1+ microglia cells after repeated peripheral administration of LPS for seven days was observed in cortex, hippocampus and corpus callosum of TNFR2-/- mice..........................67
Figure 18. Markedly changes of TNFR2-/- microglia morphology in response to repeated LPS injection.........68
Figure 19. Distribution of Iba1+ microglia cells after repeated peripheral administration of LPS for seven days was observed in cerebellum, brainstem and area postrema of TNFR2-/- mice..............................69
Figure 20. Markedly changes of TNFR2-/- microglia morphology in response to repeated LPS injection in the cerebellum, brainstem and area postrema...........70
Figure 21. Microglia expressing CD11b indicated that the TNFR2+/- microglia did not further activate after the treatment of LPS..............................71
Figure 22. Microglia expressing CD11b indicated that the TNFR2+/- microglia did not further activate after the treatment of LPS...............................72
Figure 23. Increased expression of CD11b in the brain regions of LPS-treated TNFR2-/- mice...............73
Figure 24. Increased expression of CD11b in LPS-treated TNFR2-/- mice relative to TNFR2+/-.................74
Figure 25. Increased size of glioma in the TNFR2-/- mice....75

                                    

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校外：2016-08-25公開

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