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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 呂紹俊 | |
| dc.contributor.author | Ying-Han Shen | en |
| dc.contributor.author | 沈英涵 | zh_TW |
| dc.date.accessioned | 2021-06-17T07:05:44Z | - |
| dc.date.available | 2021-08-27 | |
| dc.date.copyright | 2019-08-27 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-07-25 | |
| dc.identifier.citation | 1. Morel, D.W., P.E. DiCorleto, and G.M. Chisolm, Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis, 1984. 4(4): p. 357-64.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72770 | - |
| dc.description.abstract | 心血管疾病位居全世界死亡原因第一，目前普遍認為心血管疾病為一種發炎反應，其中 IL-1β 被認為是參與慢性發炎反應中的主要促發炎激素。心血管疾病臨床試驗 CANTOS 研究，發現給予心肌梗塞病人阻斷介白激素-1β (IL-1β) 的單株抗體可以改善心血管疾病的預後與降低復發率。促發炎激素會趨化免疫球細胞聚集在內皮下空腔導致血管內皮增厚甚至造成血管內皮細胞受損，並引發動脈粥狀硬化，血液中循環過多的低密度脂蛋白也是造成動脈粥狀硬化的危險因子之一。實驗室過去的研究顯示，在有 ST 節段升高之心肌梗塞(ST-segment elevation myocardial infarction, STEMI) 患者血液中可偵測到帶陰電性的低密度脂蛋白 (electronegative LDL, LDL (-))，且細胞實驗顯示 LDL (-) 會引起巨噬細胞產生介白激素-1β (IL-1β)。
IL-1β 的產生會透過兩條訊息途徑：第一，細胞內的 nuclear factor-κB (NF-κB) 會被活化，並作為轉錄因子促進 pro-IL-1β 和 NLRP3 發炎小體的生成；第二，NLRP3 活化後會切割 Caspase-1 並使其活化，活化的 Caspase-1 可切割 pro-IL-1β 為成熟型的 IL-1β。實驗室先前的研究指出 LDL (-) 會活化 NF-κB 和 Caspase-1。而游離脂肪酸也被認為會參與 NLRP3 的活化，促使 IL-1β 生成，然而這些實驗結果都是透過細胞株發現的。因此我們想利用較接近生理狀態的條件來探討 LDL (-) 及游離脂肪酸引起 IL-1β 產生的作用及機制。使用的細胞是由健康受試者血液分離出的周邊血單核球細胞 (peripheral blood mononuclear cells, PBMCs)，LDL (-) 則是由 STEMI 患者血液中分離得到；我們探討在體外 LDL (-) 和游離脂肪酸對 PBMCs 引起 IL-1β 產生的作用，且探討兩者在誘導 IL-1β 產生的路徑扮演何種角色。 我們將 LDL(-) 單獨或與棕櫚酸一起處理健康者的 PBMCs 24小時，分析培養液中 IL-1β 的產生。結果發現 LDL(-) 單獨處理會有些許 IL-1β產生，棕櫚酸則沒有明顯的作用；但在LDL(-) 與棕櫚酸一起處理 PBMCs 則會引起大量IL-1β產生。若事先處理 LDL (-) 一段時間再加入棕櫚酸會縮短產生 IL-1β 的時間。我們認為 LDL (-) 會作為潛在因子，可以活化病人的 PBMCs 產生 IL-1β 的第一條訊息途徑。隨後，棕櫚酸的刺激會活化第二條訊息途徑產生IL-1β。因此，我們從十個健康受試者與十個有心血管疾病病人分離出的 PBMCs 分別處理棕櫚酸24小時，結果顯示健康受試者 PBMCs 處理棕櫚酸後，並沒有明顯的 IL-1β 的產生；但病人的 PBMCs 給予棕櫚酸後會產生大量的 IL-1β。從結果推測，病人的 PBMCs 可能已經處於被 NF-κB 活化的狀態。鉀離子外流是活化第二條訊息途徑的重要因子，因此我們將 PBMCs 培養在不同濃度鉀離子溶液中，發現當鉀離子低到3 mM以下會使 IL-1β 的產量大幅提高。而在小分子抑制劑的篩選中，我們發現 voltage gated K+ (Kv) channels 抑制劑 tetraethylammonium chloride (TEA)、4-aminopyridine (4-AP) 最能有效地降低 IL-1β 產生，顯示棕櫚酸的作用可能是透過 voltage gated K+ (Kv) channels 促進鉀離子外流。另外，我們也發現 NF-κB 抑制劑 (Bay 11-7082) 和 ERK1/2 抑制劑 (U0126) 也能顯著降低 IL-1β 的量。 總結，在本篇研究中，我們透過分離健康受試者的 PBMCs，在體外實驗發現棕櫚酸和病人的 LDL (-) 會協同誘導 IL-1β 產生。LDL(-) 會有效活化 NF-κB 訊息途徑，而棕櫚酸可能是透過促進鉀離子外流的機制活化 caspase-1，兩者的加成作用使 IL-1β 產生明顯增加。我們認為在有潛在 LDL (-) 的高風險病人中，若血液中的游離脂肪酸增加會促使 IL-1β 產量明顯增加，往後的研究可以利用這個體外實驗方法來尋找適當的藥物可以抑制 IL-1β 產生，緩解發炎反應。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-17T07:05:44Z (GMT). No. of bitstreams: 1 ntu-108-R06442008-1.pdf: 1959232 bytes, checksum: 52e9ad7097e1011a0116b29869b35ba4 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 摘要 iii Abstract v 第一章、緒論 1 第一節、文獻回顧 2 (一)動脈粥狀硬化 (Atherosclerosis) 與發炎反應的關係 2 (二)LDL (-) 在發炎反應中扮演的角色 2 (三)陰電性低密度脂蛋白 (LDL (-)) 的特性 4 (四)IL-1β 與發炎反應 5 (五)IL-1β 的產生 6 (六)循環中的游離脂肪酸與發炎反應的關係 7 (七)游離脂肪酸和代謝與心血管疾病的關係 8 (八)鉀、鈣離子對於於發炎反應的影響 9 第二節、研究動機與實驗目的 11 (一)研究動機 11 (二)實驗目的 11 第二章、材料與方法 12 第一節、 實驗材料 13 第二節、 細胞培養 15 第三節、 分離脂蛋白 15 第四節、 離子交換層析法 (Ion-exchange chromatography) 分離 native-LDL 與 electronegative LDL (LDL(-)) 15 第五節、 游離脂肪酸牛血清蛋白複合物製備 16 第六節、 酵素免疫分析法 (Enzyme-linked immunosorbent assay, ELISA) 16 第七節、 細胞存活率測試 (CCK-8 assay) 16 第八節、 西方墨點法 (Western blot assay) 17 (一)細胞蛋白質萃取 17 (二)蛋白質定量 17 (三)十二烷基硫酸鈉聚丙烯醯胺凝膠電泳 (sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PA-BSAGE) 17 (四)半濕性蛋白質轉印法 18 (五)抗體結合與冷光訊號分析 18 第九節、 Caspase-1 活性試驗 18 第十節、 膜電位螢光染色 19 第十一節、利用流式細胞儀針對膜電位螢光做定量 19 第十二節、Potassium/Calcium free buffer製備 20 第十三節、統計分析 20 第三章、結果 21 第一節、人類 LDL (-) 和 棕櫚酸 (Palmitic acid, PA-BSA) 會協同促進健康受試者的 PBMCs 產生更高量的 IL-1β 22 第二節、在 PBMCs 中 PA-BSA 會透過活化 Caspase-1 來誘導 IL-1β大量產生 23 第三節、病人 LDL (-) 和 PA-BSA 對於健康受試者的 PBMCs 產生 IL-1β 量有劑量關係 23 第四節、不同時間點加入LDL (-) 和 PA-BSA 於健康受試者的 PBMCs 中產生的 IL-1β 的影響 23 第五節、心臟病病人的血液中可能潛藏 LDL (-) 並刺激 (priming) 免疫球細胞，因此外加 PA-BSA 便可誘導較高的 IL-1β 產生 24 第六節、在低濃度的鉀離子環境中，加入病人 LDL (-) 和 PA-BSA 於健康受試者的 PBMCs 中會產生大量的 IL-1β 24 第七節、非選擇性的鉀離子通道抑制劑 (TEA 和 4-AP) 可以有效抑制 PBMCs 產生的 IL-1β 25 第八節、抑制細胞內的 MEK/ERK 訊息路徑，可以有效抑制 PBMCs 產生的 IL-1β 26 第九節、逐漸增加胞外鈣離子會使 LDL (-) 和 PA-BSA 偕同刺激 PBMCs 產生 IL-1β 的量下降 26 第十節、與其他游離脂肪酸比較下，PA-BSA 和 LDL (-) 對於 PBMCs 產生 IL-1β 的加乘作用作為顯著 26 第十一節、PA-BSA 與 LDL (-) 誘導 PBMCs 協同刺激 IL-1β 的產生需要 NF κB 的活化，但並非透過 phagocytosis 和 lysosomal degradation 27 第十二節、PA-BSA 與 LDL (-) 可能不是透過改變膜電位影響 IL-1β 的生成 28 第四章、討論 29 第一節、PA-BSA 和 LDL (-) 可能是造成心血管疾病的潛在發炎因子 30 第二節、PA-BSA、LDL (-)、IL-1β 三者之間的交互作用 31 第三節、不同胞外離子濃度誘導 PBMCs 發炎的情況 31 第四節、總結 33 第五章、圖表 34 第六章、參考文獻 51 | |
| dc.language.iso | zh-TW | |
| dc.subject | 心血管疾病 | zh_TW |
| dc.subject | 巨噬細胞 | zh_TW |
| dc.subject | 棕櫚酸 | zh_TW |
| dc.subject | 陰電性低密度脂蛋白 | zh_TW |
| dc.subject | 介白激素-1β | zh_TW |
| dc.subject | palmitic acid | en |
| dc.subject | macrophage | en |
| dc.subject | free fatty acid | en |
| dc.subject | electronegative LDL | en |
| dc.subject | cardiovascular disease | en |
| dc.title | 棕櫚酸與陰電性低密度脂蛋白 (electronegative LDL) 協同促進人類單核細胞產生介白素-1β的機轉 | zh_TW |
| dc.title | Mechanisms underlying the synergistic induction of IL-1β by palmitic acid and electronegative LDL in human peripheral blood mononuclear cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 張博淵,李啟明,李安生 | |
| dc.subject.keyword | 心血管疾病,巨噬細胞,棕櫚酸,陰電性低密度脂蛋白,介白激素-1β, | zh_TW |
| dc.subject.keyword | cardiovascular disease,macrophage,free fatty acid,palmitic acid,electronegative LDL, | en |
| dc.relation.page | 63 | |
| dc.identifier.doi | 10.6342/NTU201901954 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-07-26 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| Appears in Collections: | 生物化學暨分子生物學科研究所 | |
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|---|---|---|---|
| ntu-108-1.pdf Restricted Access | 1.91 MB | Adobe PDF |
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