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研究生:吳忠耀
研究生(外文):Wu, Chung-Yao
論文名稱:評估Tris DBA 對免疫複合物所導致之腎臟疾病的療效
論文名稱(外文):Assessment of therapeutic effects of Tris DBA in immune complexmediatedrenal disorders
指導教授:陳安陳安引用關係
指導教授(外文):Chen, Ann
口試委員:陳安賈淑敏花國鋒楊安航吳家兆
口試委員(外文):Chen, AnnKa, Shuk-ManHua, Kuo-FengYang, An-HangWu, Chia-Chao
口試日期:2020-05-15
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:81
中文關鍵詞:慢性腎臟病免疫複合物所導致之腎臟疾病IgA腎病變狼瘡腎炎三(二亞苄基丙酮)二鈀絲裂素活化蛋白激酶自噬作用NLRP3發炎體
外文關鍵詞:Chronic kidney disease (CKD)Iimmune complex-mediated renal disordersIgA nephropathy (IgAN)Lupus nephritis (LN)Tris (Dibenzylideneacetone) dipalladium (Tris DBA)mitogen activated protein kinase (MAPK)autophagyNLRP3 inflammasome
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目 錄
頁次
正文目錄 ................................................................................................. I
圖目錄 .................................................................................................... V
中文摘要 ............................................................................................... VI
英文摘要 ............................................................................................ VIII
第一章、緒言 ......................................................................................................... 1
第一節 慢性腎臟病(Chronic Kidney Disease, CKD) ....................................... 1
壹、慢性腎臟病之定義與免疫複合物所引起之腎炎 ............................................. 1
貳、IgA腎病變(IgA nephropathy, IgAN) ............................................................ 2
參、 狼瘡腎炎(Lupus nephritis, LN)....................................................................... 2
肆、 IgA腎病變及狼瘡腎炎之治療............................................................................ 3
第二節IgA腎病變及狼瘡腎炎小鼠模式................................................................... 4
壹、誘發型IgA 腎病變小鼠模式............................................................................... 4
貳、加速惡化型狼瘡腎炎(Accelerated and severe lupus nephritis, ASLN)及自發型狼瘡腎炎(Spontaneous LN, spLN)小鼠模式..................................................... 4
第三節NLRP3 發炎體(NLR family pyrin domain containing 3 inflammasome, NLRP3 inflammasome) ......................................................................................... 5
第四節 自噬作用(Autophagy) ........................................................................... 5
第五節Sirtuin (SIRT) 1 和SIRT3 .......................................................................... 5
第六節 Tris (dibenzylideneacetone) dipalladium(Tris DBA)………………... 6
第七節 研究動機與目的............................................................................................ 6
第二章、 材料與方法
第一節 Tris DBA 取得及製備 ................................................................................. 7
第二節 製備IgA 抗體及PnC 抗原 ........................................................................ 7
第三節 動物模式及實驗設計 ................................................................................... 8
壹、誘發型IgA 腎病變小鼠模式 ............................................................................ 8
貳、加速惡化型狼瘡腎炎(Accelerated and severe lupus nephritis, ASLN)及自發型狼瘡腎炎(Spontaneous LN, spLN)小鼠模式 ................................................... 8
第三節 腎功能及蛋白尿測定 ................................................................................... 9
第四節 腎臟病理學分析 ......................................................................................... 10
第五節 免疫組織化學染色及免疫螢光分析 ......................................................... 10
第六節 西方墨點轉漬法 ......................................................................................... 11
第七節 抽取腎臟組織核糖核酸及即時聚合酶鏈鎖反應 .............................................................................................................................. 12
第八節 流式細胞儀分析 ........................................................................................ 12
第九節 T 細胞增生測定 ........................................................................................ 13
第十節 調控型T細胞體外抑制試驗 .................................................................... 13
第十一節 LPS / ATP誘發的急性腹膜炎 .............................................................. 14
第十二節 細胞培養.................................................................................................. 15
壹、巨噬細胞株(J774A.1).................................................................................. 15
貳、骨髓分化之樹突狀細胞(Bone marrow derived dendritic cells, BMDCs)
第十三節 活性氧化物測定 ................................................................................... 16
第十四節 小鼠血清或細胞上清液中IL-1β,TNF-α,IL-6和抗dsDNA自體抗體濃度之偵測 ......................................................................................................... 16
第十五節 數據分析 ............................................................................................... 16
第三章、結果 ......................................................................................................... 17
第一節 Tris DBA治療IgA腎病變小鼠模式 ...................................................... 17
壹、Tris DBA治療IgA腎病變小鼠之腎功能,蛋白尿和腎臟病理分析................................................................................................................................ 17
貳、Tris DBA抑制IgA腎病變小鼠腎臟組織中的NLRP3發炎體之活化並促進自噬作用 .......................................................................................................................17
參、Tris DBA抑制腎臟組織和巨噬細胞中的ROS產生 .................................... 18
肆、Tris DBA抑制了巨噬細胞中的NLRP3發炎體的活化 ............................... 19
伍、Tris DBA促進SIRT1和SIRT3所引發之自噬作用來抑制了NLRP3發炎體的活化............................................................................................................................ 20
第二節 Tris DBA治療加速惡化型狼瘡腎炎及自發型狼瘡腎炎小鼠模式 ...............................................................................................................................21
壹、Tris DBA治療加速惡化型狼瘡腎炎小鼠模式之腎功能,蛋白尿和腎臟病理分析 ...............................................................................................................................21
貳、Tris DBA條控加速惡化型狼瘡腎炎小鼠模式之T細胞及B細胞活化 .... 22
參、Tris DBA抑制了BMDC的活化以及BMDC所導致的輔助性T細胞增殖/分化............................................................................................................................... 22
肆、在ASLN小鼠中Tris DBA透過促進自噬作用來抑制的NLRP3發炎體活化 ............................................................................................................................. 23
伍、Tris DBA抑制ASLN小鼠的ROS生成並增強其抗氧化活性 ............................................................................................................................ 24
陸、Tris DBA抑制MAPK(ERK,JNK)所導引的NLRP3發炎體的第一訊型路徑活化...................................................................................................................... 25
柒、自噬作用與NLRP3發炎路徑的交互作用.................................................... 25
捌、Tris DBA治療自發型狼瘡腎炎(Spontaneous LN, spLN)小鼠模式....... 26
第四章、討論 ....................................................................................................... 28
第一節 Tris DBA 於IgA 腎病變的治療效果 .................................................. 28
第二節 Tris DBA 於加速惡化型及自發型狼瘡腎炎的治療效果 ...................28
第五章、結論 ..................................................................................................... 29
第六章、參考文獻 ............................................................................................. 30
圖 ........................................................................................................................ 36
附錄 .................................................................................................................... 49

圖目錄
頁次
圖 1、Tris DBA顯著改善IgA腎病變之腎功能、腎臟組織形態學及巨噬細胞和T細胞浸潤................................................................................................................. 36
圖2、Tris DBA促進IgA腎病變腎臟自噬作用並抑制NLRP3發炎體的活化..37
圖3、Tris DBA 抑制IgA腎病變之氧化壓力並促進抗氧化路經的活化………38
圖4、Tris DBA 抑制巨噬細胞中MAPK (ERK, JNK)所導引之NLRP3第一訊息路徑之活化................................................................................................................. 39
圖5、Tris DBA 經由自噬作用抑制NLRP3發炎體的活化................................. 40
圖6、Tris DBA 透過SIRT1和 SIRT3所誘發之自噬作用來抑制巨噬細胞中NLRP3發炎體之活化............................................................................................... 41
圖7、Tris DBA顯著改善加速惡化行狼瘡腎炎之腎功能、腎臟組織形態學....... 42
圖8、Tris DBA抑制T cell功能及骨髓所分化之樹突狀細胞活化和樹突狀細胞所導引之輔助型T細胞之增生及分化......................................................................... 43
圖9、Tris DBA促進加速惡化型狼瘡腎炎腎臟自噬作用並抑制NLRP3發炎體的活化..............................................................................................................................44
圖10、 Tris DBA 抑制加速惡化行狼瘡腎炎腎臟氧化壓力並促進抗氧化路徑的活化..............................................................................................................................45
圖11、Tris DBA 抑制巨噬細胞中MAPK (ERK, JNK)所導引之NLRP3發炎體第一訊息路徑之活化..................................................................................................46
圖12、Tris DBA 調控巨噬細胞中自噬作用與NLRP3發炎體之交互作用........47
圖13、Tris DBA顯著改善自發性NZB / W F1小鼠,狼瘡腎炎疾病進展/嚴重程度..................................................................................................................................48

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