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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 康照洲(Jaw-Jou Kang) | |
| dc.contributor.author | Cheng Jhan | en |
| dc.contributor.author | 詹晟 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:00:56Z | - |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-15 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17205 | - |
| dc.description.abstract | 奈米物質在人體內的作用情形與一般物質具有相當大的差異，當物質奈米化後，其大小、表面積、活性及物化特性會隨之改變，在人體內的吸收、分佈及毒性也會發生改變，因此對人類的健康和生態環境產生許多潛在的風險。奈米粒子通常小於100 nm，更容易被人體吸收，並且較容易穿透血管壁直接進入人體血液循環，甚至能穿透胃腸道上皮或血腦障壁 (blood-brain barrier, BBB) 造成更嚴重的傷害。
我們的研究主要是為了解奈米物質是否會造成血腦障壁對物質的通透性增加，並且探討其機制。我們利用人類臍靜脈內皮細胞 (human umbilical vein endothelial cells, HUVECs) 當作細胞實驗模式，並暴露於氧化鋅、銀及金三種金屬之非奈米及奈米粒子。首先，利用了細胞通透性試驗 (in vitro cell permeability assay) 觀察內皮細胞通透能力的影響，發現在奈米金的處理下，細胞對於大分子物質的通透性有顯著的增加，然而非奈米及其他奈米粒子皆無明顯之變化。此外，也利用小鼠實驗模式觀察奈米物質在活體中對血腦障壁通透性的影響，結果證明當尾靜脈注射奈米金後，確實造成腦部微血管血管壁的通透性增加，顯示奈米金確實會造成血腦障壁的通透。接著，進行細胞內機轉之探討，我們發現細胞中之緊密連接蛋白 (tight junctions, TJs) 會隨著處理劑量與時間的增加有著減少的趨勢；並且利用細胞免疫螢光染色法 (immunofluorescence analysis) 觀察也可發現細胞TJs的結構較不完整；因此細胞通透性的上升與細胞連接減少所導致的間隙增加有著密切的相關性。另外，我們便探討TJs表現量下降之機轉，當利用26S proteasome之抑制劑MG132抑制其活性，且同時處理了奈米金後發現TJs並沒有減少的現象，因此奈米金所引發的TJs減少是經由26S proteasome所降解的。然而，在TJs之訊息傳遞調控上，當處理了PKCζ之抑制劑Go6983後，TJs表現量有下降的趨勢，因此PKCζ對於TJs的調控扮演了重要角色；而當處理了奈米金之下，PKCζ的磷酸化有減少之趨勢，顯示PKCζ的活性降低，因此得知奈米金所引發的TJs減少是經由PKCζ作為中間之訊息傳遞。 綜合以上實驗結果，我們證實了奈米金會引發血腦障壁的通透性增加，並且是經由調控PKCζ的磷酸化而導致活性上之改變而影響TJs的穩定性，較容易被降解，並且是經由26S proteasome之途徑，最後導致內皮細胞間之連接減少促使細胞對於物質的通透性增加。 | zh_TW |
| dc.description.abstract | Nanoparticles have smaller size and different physical-chemical characteristics, so the absorption, distribution and toxicity may differ from its bulk material in the human body. Therefore, nanoparticles may cause health risks which are different from those of similar materials in micro or macro form. The blood-brain barrier (BBB) formed by endothelial cells is lining the cerebral microvessels, and has impermeability structure that regulates molecular traffic.
Since nanoparticles are so small that possibly cross the BBB or destroy the impermeability structure, in this study, we investigated whether three commonly used metal particles including gold, silver and zinc oxide could disrupt BBB and increase permeability. Human umbilical vein endothelial cells (HUVECs) were treated with gold, silver, zinc oxide non-nanoparticles and nanoparticles. Cells permeability was increased when treated with gold nanoparticles by in vitro cell permeability assay, while silver and zinc oxide nanoparticles did not. Furthermore, we used in vivo BBB permeability assay and found that injection of gold nanoparticles into mice through tail intravenous injection, had more permeability compare with non-nanoparticles in the brain, indicating the BBB disruption. We found that gold nanoparticles reduce tight junctions (TJs) protein expression such as occludin, claudin-5 and JAM-1, but had no effect on adherens junctions (AJs) protein such as VE-cadherin. Moreover, the structures of TJs had no integrity after treatment with gold nanoparticle by immunofluorescence analysis. TJs protein expression didn’t decrease after pretreatment with 26S proteasome inhibitor, so gold nanoparticle-induced TJs degradation were thought 26S proteasome pathway. Further, we focused on the TJs regulation signaling, the TJs protein expression were decrease after pretreatment with PKCζ inhibitor, indicated that PKCζ was positive correlation with TJs. We indicated that phosphorylation level of PKCζ were down-regulation when treatment of gold nanoparticles, Therefore, gold nanoparticles could down-regulated the activity of PKCζ, and that resulted in TJs instability. Our results showed that gold nanoparticles could cause BBB permeability increase via protein level regulation of TJs. The gold nanoparticles induced TJs protein decrease through regulation level of phosphorylation of PKCζ, and the low level of phosphorylated PKCζ affected the TJs stability, caused TJs degradation via 26S proteasome. Finally, the endothelial cells junctions decrease brought cell permeability increase. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:00:56Z (GMT). No. of bitstreams: 1 ntu-102-R00447007-1.pdf: 3217678 bytes, checksum: c81864f7c5b044f9d9cdbb714ba8f4b0 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 圖表目錄 v 中文摘要 vi 英文摘要 viii 縮寫表 x 第一章 緒論 (Introduction) 1 1.1 奈米科技 (Nanotechnology) 2 1.2 奈米毒理學 (Nanotoxicology) 5 1.3 奈米粒子 (Nanoparticles, NPs) 7 1.4 血腦障壁 (Blood-brain barrier, BBB) 9 1.5 連接蛋白 (Cell junctions) 11 1.6 研究動機 14 第二章 材料與方法 (Materials and Methods) 15 2.1 材料 16 2.1.1 細胞與動物 16 2.1.2 藥品與試劑 16 2.1.3 抗體與酵素 18 2.1.4 儀器 18 2.2 方法 19 2.2.1 穿透式電子顯微鏡 (Transmission electron microscopy, TEM) 19 2.2.2 人類臍靜脈內皮細胞 (HUVECs) 分離及培養 19 2.2.3 細胞存活率試驗 (Cell viability assay) 20 2.2.4 細胞通透性試驗 (In vitro cell permeability assay) 21 2.2.5 活體血腦障壁通透性試驗 (In vivo BBB permeability assay) 21 2.2.6 西方墨點法 (Western blotting analysis) 21 2.2.7 細胞免疫螢光染色法 (Immunofluorescence analysis) 22 2.2.8 反轉錄聚合酶鏈鎖反應 (RT-PCR) 23 2.2.9 統計分析 24 第三章 結果 (Results) 25 3.1 非奈米及奈米粒子粒徑大小分析 26 3.2 非奈米及奈米粒子對人類臍靜脈內皮細胞之細胞存活率 26 3.3 奈米金增加人類臍靜脈內皮細胞之細胞障壁對物質的通透性 28 3.4 奈米金增加血腦障壁對物質的通透性 29 3.5 奈米金對於細胞AJs之表現沒有影響 29 3.6 奈米金降低細胞TJs之表現 30 3.7 奈米金破壞細胞TJs結構的完整性 31 3.8 奈米金無法降低細胞TJs mRNA之表現 32 3.9 奈米金引發細胞TJs的降解是經26S proteasome之途徑 32 3.10 奈米金降低細胞TJs的表現是經由調控PKCζ之活性 33 第四章 討論 (Discussion) 35 4.1 奈米粒子引起之細胞毒性 36 4.2 奈米金引發血腦障壁通透之機制 37 4.3 奈米金引發細胞TJs表現減少之機制 39 4.4 奈米金之藥理及毒理學 43 第五章 結論 (Conclusion) 45 參考文獻 (References) 47 圖表 (Figures and Tables) 64 | |
| dc.language.iso | zh-TW | |
| dc.title | 奈米金引發血腦障壁通透之機制探討 | zh_TW |
| dc.title | Studies on the Mechanisms of Gold Nanoparticle-Induced Blood-Brain Barrier Permeability | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄭幼文(Yu-Wen Cheng),劉俊仁(Jun-Jen Liu) | |
| dc.subject.keyword | 奈米物質,奈米金,血腦障壁,通透性,緊密連接蛋白, | zh_TW |
| dc.subject.keyword | gold nanoparticles,blood-brain barrier,permeability,tight junctions,occludin,JAM-1,claudin-5, | en |
| dc.relation.page | 89 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-08-16 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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