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題名 發炎的機制以及其在中樞代謝調控中的作用研究
The Study of the Mechanisms of Inflammation and Its roles in Central Controls of Metabolism
作者 章學榛
貢獻者 陳紹寬
章學榛
關鍵詞 干擾素誘導跨膜蛋白
發炎
POMC神經元
促發炎細胞因子
代謝調控
IFITM
Inflammation
POMC neuron
Proinflammatory cytokines
Metabolic signaling
日期 2018
上傳時間 27-Aug-2018 14:47:47 (UTC+8)
摘要 本研究包括兩個部分。第一部分是發現Ifitm基因剔除鼠中產生的自發性發炎反應表型。Ifitm基因是一組會受干擾素所誘導表現的基因，干擾素刺激後所轉譯出的蛋白質在抗病毒功能中有著重要作用。然而，這些蛋白質的生化性質和生物功能上還不清楚。在先前的研究中，剔除5個Ifitm基因的IfitmDel小鼠被用來探討Ifitm基因的生物功能，我們在IfitmDel小鼠中觀察到隨著年齡的增加會產生低度發炎，在周邊血中單核細胞活化標誌物如CD86和MHCII的水平升高。IfitmDel小鼠在文獻中被指出有肥胖和食慾過盛的表現，我們發現這些小鼠的下視丘中Nos2表現顯著增加，表示著下視丘有發炎的情況。為了測試是否是機能不全的骨髓細胞或是過多的發炎訊號引起IfitmDel小鼠低度發炎，我們取野生型小鼠及IfitmDel小鼠的骨髓，並將其誘導成巨噬細胞來，比較其對發炎刺激的反應。在脂多醣體(LPS)和干擾素-γ(Interferon-γ)的刺激下，IfitmDel小鼠骨髓誘導巨噬細胞被活化的程度顯著較高。我們的結果顯示IFITM蛋白在巨噬細胞中具有調節發炎反應的功能，Ifitm基因的缺失導致在刺激下有較強烈的發炎反應。本研究的第二部分是研究促發炎細胞因子如何改變POMC神經元的代謝信號。位於下視丘弓狀核的POMC神經元在飲食調控和能量平衡中扮演重要角色，透過接受周邊代謝信號，如瘦蛋白和胰島素，來調控食慾下降並增加能量消耗，最近的研究中表明發炎可能會干擾POMC神經元中的代謝調節路徑。在我們的研究中，檢測了促發炎因子的增加如何影響mHypoA-POMC / GFP細胞株的代謝信號傳導。此外，考慮到造成發炎的物質並不局限於單一種促發炎細胞因子，所以將以LPS處理過的誘導巨噬細胞培養液應用為條件培養液加入POMC神經元中，此條件培養液中含有促炎細胞因子混合物。我們首先檢測POMC神經元對混合促炎細胞因子的反應，調控POMC神經元厭食反應的基因，如：POMC和Socs3，在發炎信號的刺激下升高。之後檢測在有條件培養液的環境下，POMC神經元中瘦素或胰島素誘導的信號傳導途徑的活化是否會受影響，瘦素或胰島素信號傳導在促炎細胞因子存在下會被破壞。另外，POMC神經元中的關鍵代謝調節蛋白：單磷酸腺苷活化蛋白質激酶(AMPK)的活化會被促炎細胞因子抑制。綜合上述觀察結果，我們認為POMC神經元的代謝調控會在發炎的環境下遭到破壞。
This study consists of two major parts. The first part is to characterize the inflammation developed in Ifitm genes knockout mutants. Ifitm genes are a group of interferon inducible genes that are transcriptional activated upon interferon stimulation and play important roles in interferon meditated antiviral functions. However, the biochemical properties and other biological functions of these proteins are not fully understood. Previously IfitmDel mutant mice that lack 5 Ifitm genes were generated to investigate the biological functions of Ifitm genes. We recently observed age dependent low-grade inflammation phenotype in IfitmDel mice. Mutants at 4-month of age started to exhibit elevated levels of monocyte activation markers such as CD86 and MHCII in peripheral blood. Obesity and hyperphagia have previously been reported in IfitmDel mutants. The expression of hypothalamic nos2 is upregulated in the mutants, indicating that hypothalamic inflammation is also developed. To test whether inflammation is caused by malfunctioned mutant myeloid cells or by excessive inflammatory signals, we further generate bone marrow derived macrophages from both IfitmDel mutants and wild type controls. Upon LPS and interferon-γ stimulation, mutant macrophages are drastically activated and the activation status is significantly higher than that of wild type macrophages. Our data suggest the anti-inflammatory roles of IFITM proteins. Ablating Ifitm genes augment the inflammatory response upon stimulation. The second part of this study is to investigate how proinflammatory cytokines altered the metabolic signaling in POMC neurons. POMC neurons in arcuate nucleus play pivotal roles in feeding controls and energy homeostasis. This group of neurons respond to peripheral metabolic signals, such as leptin and insulin, and mediate the anorexigenic response and increase energy expenditure in the hypothalamus. Recently accumulating data suggest that inflammation might interrupt metabolic regulations by affecting this group of neurons. In this study, we examined how increase of proinflammatory molecules influence metabolic signaling in the cell line mHypoA-POMC/GFP, which is generated by immortalizing the primary hypothalamic POMC neurons cultures. Also, considering that the effect of inflammation might not be limited to single kind of proinflammatory cytokines, we applied conditioned medium of LPS-primed macrophages, which contained a mixture of proinflammatory cytokines, to the POMC neuron culture. We first examined the response of the POMC neurons to the mixed proinflammatory cytokines. The genes mediating anorexigenic response of POMC neurons, such as POMC and Socs3, are elevated upon the stimulation of the inflammatory signals. Additionally, the activation of signaling pathways of the POMC neurons induced by leptin or insulin were examined with the conditioned medium. Both leptin or insulin signaling are disrupted at the presence of proinflammatory cytokines. Also, the activation of AMP-activated protein kinase (AMPK), a key metabolic regulator in POMC neurons, is also inhibited by proinflammatory cytokines. Combining all the observations, we conclude that metabolic signaling of POMC neurons are disrupted with inflammation.
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描述 碩士
國立政治大學
神經科學研究所
104754006
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0104754006
資料類型 thesis
dc.contributor.advisor 陳紹寬zh_TW
dc.contributor.author (Authors) 章學榛zh_TW
dc.creator (作者) 章學榛zh_TW
dc.date (日期) 2018en_US
dc.date.accessioned 27-Aug-2018 14:47:47 (UTC+8)-
dc.date.available 27-Aug-2018 14:47:47 (UTC+8)-
dc.date.issued (上傳時間) 27-Aug-2018 14:47:47 (UTC+8)-
dc.identifier (Other Identifiers) G0104754006en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/119578-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 104754006zh_TW
dc.description.abstract (摘要) 本研究包括兩個部分。第一部分是發現Ifitm基因剔除鼠中產生的自發性發炎反應表型。Ifitm基因是一組會受干擾素所誘導表現的基因，干擾素刺激後所轉譯出的蛋白質在抗病毒功能中有著重要作用。然而，這些蛋白質的生化性質和生物功能上還不清楚。在先前的研究中，剔除5個Ifitm基因的IfitmDel小鼠被用來探討Ifitm基因的生物功能，我們在IfitmDel小鼠中觀察到隨著年齡的增加會產生低度發炎，在周邊血中單核細胞活化標誌物如CD86和MHCII的水平升高。IfitmDel小鼠在文獻中被指出有肥胖和食慾過盛的表現，我們發現這些小鼠的下視丘中Nos2表現顯著增加，表示著下視丘有發炎的情況。為了測試是否是機能不全的骨髓細胞或是過多的發炎訊號引起IfitmDel小鼠低度發炎，我們取野生型小鼠及IfitmDel小鼠的骨髓，並將其誘導成巨噬細胞來，比較其對發炎刺激的反應。在脂多醣體(LPS)和干擾素-γ(Interferon-γ)的刺激下，IfitmDel小鼠骨髓誘導巨噬細胞被活化的程度顯著較高。我們的結果顯示IFITM蛋白在巨噬細胞中具有調節發炎反應的功能，Ifitm基因的缺失導致在刺激下有較強烈的發炎反應。本研究的第二部分是研究促發炎細胞因子如何改變POMC神經元的代謝信號。位於下視丘弓狀核的POMC神經元在飲食調控和能量平衡中扮演重要角色，透過接受周邊代謝信號，如瘦蛋白和胰島素，來調控食慾下降並增加能量消耗，最近的研究中表明發炎可能會干擾POMC神經元中的代謝調節路徑。在我們的研究中，檢測了促發炎因子的增加如何影響mHypoA-POMC / GFP細胞株的代謝信號傳導。此外，考慮到造成發炎的物質並不局限於單一種促發炎細胞因子，所以將以LPS處理過的誘導巨噬細胞培養液應用為條件培養液加入POMC神經元中，此條件培養液中含有促炎細胞因子混合物。我們首先檢測POMC神經元對混合促炎細胞因子的反應，調控POMC神經元厭食反應的基因，如：POMC和Socs3，在發炎信號的刺激下升高。之後檢測在有條件培養液的環境下，POMC神經元中瘦素或胰島素誘導的信號傳導途徑的活化是否會受影響，瘦素或胰島素信號傳導在促炎細胞因子存在下會被破壞。另外，POMC神經元中的關鍵代謝調節蛋白：單磷酸腺苷活化蛋白質激酶(AMPK)的活化會被促炎細胞因子抑制。綜合上述觀察結果，我們認為POMC神經元的代謝調控會在發炎的環境下遭到破壞。zh_TW
dc.description.abstract (摘要) This study consists of two major parts. The first part is to characterize the inflammation developed in Ifitm genes knockout mutants. Ifitm genes are a group of interferon inducible genes that are transcriptional activated upon interferon stimulation and play important roles in interferon meditated antiviral functions. However, the biochemical properties and other biological functions of these proteins are not fully understood. Previously IfitmDel mutant mice that lack 5 Ifitm genes were generated to investigate the biological functions of Ifitm genes. We recently observed age dependent low-grade inflammation phenotype in IfitmDel mice. Mutants at 4-month of age started to exhibit elevated levels of monocyte activation markers such as CD86 and MHCII in peripheral blood. Obesity and hyperphagia have previously been reported in IfitmDel mutants. The expression of hypothalamic nos2 is upregulated in the mutants, indicating that hypothalamic inflammation is also developed. To test whether inflammation is caused by malfunctioned mutant myeloid cells or by excessive inflammatory signals, we further generate bone marrow derived macrophages from both IfitmDel mutants and wild type controls. Upon LPS and interferon-γ stimulation, mutant macrophages are drastically activated and the activation status is significantly higher than that of wild type macrophages. Our data suggest the anti-inflammatory roles of IFITM proteins. Ablating Ifitm genes augment the inflammatory response upon stimulation. The second part of this study is to investigate how proinflammatory cytokines altered the metabolic signaling in POMC neurons. POMC neurons in arcuate nucleus play pivotal roles in feeding controls and energy homeostasis. This group of neurons respond to peripheral metabolic signals, such as leptin and insulin, and mediate the anorexigenic response and increase energy expenditure in the hypothalamus. Recently accumulating data suggest that inflammation might interrupt metabolic regulations by affecting this group of neurons. In this study, we examined how increase of proinflammatory molecules influence metabolic signaling in the cell line mHypoA-POMC/GFP, which is generated by immortalizing the primary hypothalamic POMC neurons cultures. Also, considering that the effect of inflammation might not be limited to single kind of proinflammatory cytokines, we applied conditioned medium of LPS-primed macrophages, which contained a mixture of proinflammatory cytokines, to the POMC neuron culture. We first examined the response of the POMC neurons to the mixed proinflammatory cytokines. The genes mediating anorexigenic response of POMC neurons, such as POMC and Socs3, are elevated upon the stimulation of the inflammatory signals. Additionally, the activation of signaling pathways of the POMC neurons induced by leptin or insulin were examined with the conditioned medium. Both leptin or insulin signaling are disrupted at the presence of proinflammatory cytokines. Also, the activation of AMP-activated protein kinase (AMPK), a key metabolic regulator in POMC neurons, is also inhibited by proinflammatory cytokines. Combining all the observations, we conclude that metabolic signaling of POMC neurons are disrupted with inflammation.en_US
dc.description.tableofcontents 謝誌 i
摘要 ii
Abstract iii
目次 v
圖次 viii
縮寫對照表 x
第一章 緒 論 1
第一節 文獻回顧 1
一、干擾素誘導跨膜蛋白 (Interferon induced transmembrane proteins, IFITMs) 1
二、炎症機制 (Inflammation mechanisms) 3
三、巨噬細胞的發育和在發炎中的生物學作用 (Macrophage development and biological roles in inflammation 5
四、代謝所引發的發炎和肥胖的關係 (Inflammation metabolism and obesity) 7
五、中央代謝調節系統和POMC神經元 (Central metabolic regulating system and POMC neurons) 8
六、下視丘炎症 (Hypothalamic inflammation) 9
第二節 論文目的及研究策略 10
一、研究目的及動機 10
二 、實驗設計 11
第二章 材料與方法 12
第一節 實驗動物 12
第二節 瘦素抗性實驗 (Leptin resistance) 12
第三節 細胞培養 12
一、細胞培養 12
二、細胞繼代培養與計數 13
第四節 藥物處理 14
第五節 西方點墨法 (Western blot) 14
一、蛋白質萃取 14
二、蛋白質濃度測定 15
三、樣品配置 15
四、鑄膠和十二烷基硫酸鈉聚丙烯酰胺凝膠電泳 (Sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE) 15
五、蛋白質轉漬 (Transfer) 16
六、免疫反應 (Immunoblotting) 16
七、顯像及分析 17
第六節 定量即時聚合酶鏈鎖反應 (Quantitative real time polymerase chain reaction, Q-PCR) 17
一、RNA萃取及濃度測定 17
二、逆轉錄聚合酵素鏈鎖反應(reverse transcription-PCR, RT-PCR) 18
三、定量即時聚合酶鏈鎖反應 18
第七節 流式細胞儀檢測 (Flow cytometer) 19
一、樣品備置 19
二、樣品分析 20
第八節 統計分析 22
第三章 實驗結果 23
第一節 在IfitmDel突變體中發展的炎症型態 23
第二節 Ifitm基因缺失對於造血作用的改變 24
第三節 Ifitm基因缺失對於骨髓細胞誘導巨噬細胞功能產生的影響 26
第四節 Ifitm基因缺失小鼠表現瘦素不敏感 28
第五節 mHypoA-POMC / GFP-1細胞對瘦素的反應 28
第六節 mHypoA-POMC / GFP-1細胞對胰島素的反應 30
第七節 發炎物質對mHypoA-POMC / GFP-1細胞中AMPK路徑的改變 31
第四章 討 論 33
實驗圖表 36
參考文獻 54
附錄 59		zh_TW
dc.format.extent 2265392 bytes-
dc.format.mimetype application/pdf-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0104754006en_US
dc.subject (關鍵詞) 干擾素誘導跨膜蛋白zh_TW
dc.subject (關鍵詞) 發炎zh_TW
dc.subject (關鍵詞) POMC神經元zh_TW
dc.subject (關鍵詞) 促發炎細胞因子zh_TW
dc.subject (關鍵詞) 代謝調控zh_TW
dc.subject (關鍵詞) IFITMen_US
dc.subject (關鍵詞) Inflammationen_US
dc.subject (關鍵詞) POMC neuronen_US
dc.subject (關鍵詞) Proinflammatory cytokinesen_US
dc.subject (關鍵詞) Metabolic signalingen_US
dc.title (題名) 發炎的機制以及其在中樞代謝調控中的作用研究zh_TW
dc.title (題名) The Study of the Mechanisms of Inflammation and Its roles in Central Controls of Metabolismen_US
dc.type (資料類型) thesisen_US
dc.relation.reference (參考文獻) 參考文獻
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dc.identifier.doi (DOI) 10.6814/THE.NCCU.IN.003.2018.C05-