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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李心予 | zh_TW |
| dc.contributor.advisor | Hsinyu Lee | en |
| dc.contributor.author | 黃奕勛 | zh_TW |
| dc.contributor.author | Yi-Xun Huang | en |
| dc.date.accessioned | 2023-08-30T16:17:32Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-08-30 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-07-17 | - |
| dc.identifier.citation | 1. Hirschhorn T, Stockwell BR. The development of the concept of ferroptosis. Free Radic Biol Med. 2019;133:130-143.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89197 | - |
| dc.description.abstract | 鐵依賴型細胞死亡為一種新發現因脂質過氧化以及鐵的過度累積所導致之調節性細胞死亡。它已經被證明與胚胎紅血球生成及衰老過程有關。水解磷酸脂(LPA)為一種脂質生長因子，可以透過活化多種G蛋白偶連受體來調控各種生理功能。在我們先前的研究表明，第三型水解磷酸脂受器(LPA3)已經被證明可以改善氧化反應並加速恢復小鼠急性貧血。由於兩個過程均與鐵離子密切相關，所以我們假設活化第三型水解磷酸脂受器可以避免細胞發生鐵依賴型細胞死亡。在本篇研究中，我們利用埃拉斯汀外發性誘導人類纖維肉瘤細胞發生鐵依賴型細胞死亡。為了探討第三型水解磷酸脂受器是如何避免細胞發生鐵依賴型細胞死亡，我們利用其活化劑1-油酰基-2-O-甲基-外消旋-甘油硫代磷酸酯(OMPT)活化第三型水解磷酸脂受器以進行研究。在埃拉斯汀誘導的細胞中，與控制組相比，利用OMPT活化第三型水解磷酸脂受器會增加抗鐵依賴型細胞死亡相關蛋白的表達，例如：溶質載體家族7成員11 (SLC7A11)、穀胱甘肽過氧化物酶4 (GPX4)、鐵質氧化酶-1 (HO-1)及鐵蛋白重鍊1 (FTH1)等的表達均受到促進。此外，透過C11 BODIPY™ 581/591脂質過氧化染劑及FerroOrang染色分析，OMPT的處理減少脂質過氧化及胞內鐵離子的累積。而這些結果與利用siRNA降低第三型水解磷酸脂受器基因表達結果相符。我們更進一步的證實，在埃拉斯汀誘導的細胞中，活化第三型水解磷酸脂受器使絲裂原活化蛋白激酶(MEK)及細胞外信號調節激酶(ERK)磷酸化。此外，作為關鍵的氧化反應調節劑的核因子類紅血球2相關因子2 (NRF2)在細胞處理OMPT後蛋白質表達量也有增加。根據以上結果，活化第三型水解磷酸脂受器可能透過絲裂原活化蛋白激酶/細胞外信號調節激酶/核因子類紅血球2相關因子2信號通路，進而抑制細胞內脂質過氧化及鐵離子的累積，以防止鐵依賴型細胞死亡的發生。最後，在人類紅白血病K562細胞中也證實，第三型水解磷酸脂受器在埃拉斯汀誘導的鐵依賴型細胞死亡環境中扮演著關鍵的角色，這些研究成果提供了未來治療貧血的一項新策略。 | zh_TW |
| dc.description.abstract | Ferroptosis is a novel type of programmed cell death that caused by lipid peroxidation and iron accumulation. It has been shown to be involved in embryonic erythropoiesis and aging. Lysophosphatidic acid (LPA) is a lipid growth factor that regulates various physiological functions via activating multiple G protein-coupled receptors LPA1-6. Our previous studies demonstrated that activation of lysophosphatidic acid receptor 3 (LPA3) has been shown to ameliorate oxidative stress and accelerate the recovery of acute-anemia in mice. Since both process involve the metabolism of irons, we hypothesize that activation of LPA3 may affect cellular ferroptosis. In this study, HT-1080 fibrosarcoma cells were treated with 5 M of erastin to induce ferroptosis. LPA3 agonists 1‐Oleoyl‐2‐O‐methyl‐rac‐glycerophosphothionate (OMPT) were applied to activate LPA3 to determine the effects of LPA3 on ferroptosis process. Treatment with OMPT increased the protein expression of anti-ferroptosis genes, including solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1), and ferritin heavy chain (FTH1) in erastin-induced cells, but no effects were observed in the control group. Moreover, OMPT decreased the level of lipid peroxidation and intracellular ferrous iron accumulation, as detected by assay staining C11 BODIPY™ 581/591 Lipid Peroxidation Sensor and FerroOrange. Our observations were also validated by applying the LPAR3 siRNA in the experiments mentioned above. We further showed that activation of LPA3 led to the phosphorylation of mitogen-activated protein kinases (MEK) and extracellular signal-regulated kinases (ERK) in erastin-induced cells, which are important signaling mediators for ferroptosis activation. In addition, the protein expression level of nuclear factor erythroid 2-related factor (NRF2), a critical oxidative stress regulator, was also increased in OMPT-treated cells. Taken together, our results suggest that activation of LPA3 prevents cell ferroptosis by inhibiting lipid oxidation and iron accumulation via the MEK/ERK/NRF2 signaling pathways. Finally, we also confirmed that LPA3 plays a critical role in erastin-induced ferroptotic human erythroleukemia K562 cells, providing a novel strategy for future anemia treatment. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-08-30T16:17:32Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-08-30T16:17:32Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 論文口試委員審定書...I
致謝...II 中文摘要...III Abstract...V Introduction...01 Overview of ferroptosis...01 Glutathione/glutathione peroxidase 4 (GSH/GPX4) pathway...02 Iron metabolism...03 Erastin...04 Lysophosphatidic acid and lysophosphatidic acid receptor 3...06 LPA3 and erythropoiesis...07 Rationale...09 Materials and methods...10 Cell culture and pharmacological reagents...10 Cell viability assay...10 Intracellular ferrous iron content detection...11 Measurement of lipid ROS level...11 Western blot...12 RNA interference and transfection...13 Reverse transcription (RT) and real-time quantitative polymerase chain reaction (RT-qPCR)...13 Luciferase assay of GYPA promoter assay...14 Statistical analysis...14 Results...15 Erastin induces cytotoxicity in HT-1080 cells...15 LPA3 agonist reduces erastin-induced ferroptotic death...16 LPA3 agonist reduces erastin-induced lipid peroxidation in HT-1080 cells...17 LPA3 agonist stabilize the iron homeostasis in erastin-induced HT-1080 cells...18 LPA3 agonist protects cells from erastin-induced ferroptosis through MEK/ERK/NRF2 signaling pathway...19 Knockdown of LPAR3 leads to cells ferroptosis in HT-1080 cells...20 LPA3 promotes erythropoiesis in erastin-induced K562 cells...20 Discussion...22 References...28 Tables & Figures...41 Table. 1 Antibodies list...41 Table. 2 siRNA list...42 Table. 3 Real-time PCR primers (human)...42 Figure. 1 Erastin induces ferroptosis in HT-1080 cells...43 Figure. 2 LPA3 agonist reduces erastin-induced lipid peroxidation in HT-1080 cells..47 Figure. 3 LPA3 agonist stabilize the iron homeostasis in erastin-induced HT-1080 cells...50 Figure. 4 LPA3 agonist protects cells from erastin-induced ferroptosis through MEK/ERK/NRF2 signaling pathway...52 Figure. 5 Knockdown of LPAR3 leads to cells ferroptosis in HT-1080 cells...54 Figure. 6 LPA3 promotes erythropoiesis in erastin-induced K562 cells...56 Figure. 7 Conclusion of this study...58 | - |
| dc.language.iso | en | - |
| dc.title | 第三型水解磷酸脂受器於紅血球生成中鐵依賴型細胞死亡調控之研究 | zh_TW |
| dc.title | Investigation of the Roles of Lysophosphatidic Acid Receptor 3 in the Regulation of Ferroptosis during Erythropoiesis | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 黃偉邦;蘇純立;吳沛翊 | zh_TW |
| dc.contributor.oralexamcommittee | Wei-Pang Huang;Chun-Li Su;Pei-Yi Wu | en |
| dc.subject.keyword | 水解磷酸脂,第三型水解磷酸脂受器,鐵依賴型細胞死亡,紅血球生成,脂質過氧化,鐵離子累積, | zh_TW |
| dc.subject.keyword | Lysophosphatidic acid,Lysophosphatidic acid receptor 3,Ferroptosis,Erythropoiesis,Lipid peroxidation,Iron accumulation, | en |
| dc.relation.page | 58 | - |
| dc.identifier.doi | 10.6342/NTU202301668 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2023-07-18 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生命科學系 | - |
| 顯示於系所單位： | 生命科學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-111-2.pdf 目前未授權公開取用 | 2.61 MB | Adobe PDF |
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