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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 潘建源(Chien-Yuan Pan) | |
dc.contributor.author | Hui-Chiun Tseng | en |
dc.contributor.author | 曾惠群 | zh_TW |
dc.date.accessioned | 2021-06-15T11:44:45Z | - |
dc.date.available | 2023-09-30 | |
dc.date.copyright | 2020-08-21 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-08-13 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49731 | - |
dc.description.abstract | 近年研究發現許多神經退化性疾病,如阿茲海默症、杭丁頓氏症和帕金森氏症等的發病機制與神經炎症 (neuroinflammation) 有關,並受到神經科學家們的廣泛關注。發炎反應啟動後,炎症小體 (inflammasomes) 的形成,會活化caspase-1,進而啟動細胞焦亡機制 (pyroptosis pathway),釋放成熟的炎症細胞因子,包括IL-1β和IL-18至細胞外。我們過去的研究發現,多巴胺(dopamine, DA)會造成細胞內鋅離子濃度上升,誘導初代培養的大鼠胚胎皮質神經細胞死亡、及IL-1β基因表現增加。但是,神經炎症是否與DA誘導的細胞死亡有關尚不清楚。在本研究中,我們以初代培養的大鼠胚胎皮質神經細胞為模式,處理DA和二氫己啶 (dihydrexidine, DHX, 多巴胺D1受體促進劑),誘導細胞死亡。再以TPEN (鋅離子螯合劑),MCC950 (細胞焦亡炎症小體抑制劑) 與VX765 (caspase 1抑製劑),預處理培養的神經細胞,結果顯示這些抑制劑可減緩DA或DHX所造成的神經細胞死亡。而聚合酶鏈鎖反應和西方點墨法的結果顯示,DA或DHX處理會增加IL-1β基因與蛋白質的表現量 ; 而此增加,可以被TPEN所降低。而IL-1β的前處理,可以減少DA所造成的細胞死亡。這些結果顯示,細胞焦亡參與在D1受體與鋅離子所誘導的神經細胞死亡過程中,而過程中所釋放的IL-1β可提高神經細胞的存活率。因此如何控制細胞焦亡與IL-1β的釋放,將可提供神經退化性疾病新的治療策略。 | zh_TW |
dc.description.abstract | Neuroinflammation has attracted much attention recently in the nervous system for its association with the pathogenesis of neurodegenerative disorders like Alzheimer's, Huntington’s, and Parkinson's diseases etc. The activation of inflammation will induce the formation of inflammasomes which activates the caspase-1 resulting in the induction of pyroptosis signaling pathway and the release of matured inflammatory cytokines including IL-1β and IL-18 into the extracellular milieu. Our previous reports have shown that dopamine (DA) elevates intracellular Zn2+ concentration which is a perquisite for DA-induced cell death and enhances the mRNA level of IL-1β in cultured rat embryonic cortical neurons. However, it is unclear that neuroinflammation is involved in DA-induced cell death. In this report, we treated the primary cultured rat embryonic cortical neurons with DA and dihydrexidine (DHX), a dopamine D1 receptor agonist, to induce cell death. Pretreating the cultured neurons with TPEN, a cell permeable Zn2+ chelator, MCC950, an inflammasome blocker, and VX765, a caspase 1 inhibitor could suppress cell death induced by dopamine and DHX. The PCR and Western blot analysis showed DA and DHX treatments increased the expression levels of IL-1 in culture neuron cells. In addition, pretreating the neurons with IL-1β suppressed the DA-induced cell death. These results suggest the involvement of pyroptosis in D1 receptor-Zn2+-cell death pathway and the released IL-1β enhances the cell survival. Therefore, controlling the pyroptosis and IL-1β level can be a new therapeutic strategy for neurodegenerative diseases. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T11:44:45Z (GMT). No. of bitstreams: 1 U0001-1208202000222400.pdf: 2484033 bytes, checksum: c540ccf831f931dbf2564f4811fb0310 (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 致謝 i 中文摘要 ii Abstract iii Abbreviations 1 1. Introduction 2 1.1 Zinc homeostasis 2 1.2 Neurodegenerative disorders 4 1.3 Dopamine in neurodegeneration 5 1.4 Neuron death 7 1.5 Neuroinflammation 8 1.6 Pyroptosis 8 1.7 IL-1β signaling pathway 10 1.8 Dihydroxidine (DHX) 11 1.9 Aims 12 2. Materials and Methods 14 2.1 Chemicals 14 2.2 Primary culture of rat embryonic cortical neurons 14 2.3 Drug treatments 16 2.4 Zn2+ imaging 16 2.5 MTT assay 18 2.6 mRNA gene expression 18 2.7 Real-Time Quantitative Polymerase Chain Reaction (qPCR) 20 2.8 Western blot analysis 21 2.9 Data analysis 22 3. Results 23 3.1 Dopamine and DHX elevate intracellular Zn2+ concentration in neurons 23 3.2 A Zn2+ chelator suppresses dopamine-induced [Zn2+]i elevation 24 3.3 A Zn2+ chelator suppresses DHX-induced [Zn2+]i elevation 24 3.4 DHX-induced neuron cell death is dose dependent 25 3.5 TPEN reveres dopamine and DHX-induced neuron death 26 3.6 MCC950 recovers dopamine and DHX-induced neuron death 27 3.7 VX765 suppresses dopamine and DHX-induced neuron death 28 3.8 Zn2+ involved in dopamine-increased IL-1β gene expression by PCR 29 3.9 Zn2+ involved in dopamine-increased IL-1β gene expression by qPCR 30 3.10 Protein level of IL-1β was increased by dopamine 31 3.11 Protein level of IL-1β was increased via D1-like receptor 31 3.12 IL-1β pretreatment protects the neuron death induced by dopamine 32 4. Discussion 34 5. References 39 6. Table. 51 Table 1. PCR primers of pyroptosis-related genes 51 7. Figures 52 Fig. 1. Dopamine and DHX elevates intracellular zinc concentration 53 Fig. 2. TPEN effectively suppresses DA-induce elevation 55 Fig. 3. DHX induces elevation of the intracellular Zn2+ concentration in neurons 57 Fig. 4. DHX-induced neuron death is dose-dependent 59 Fig. 5. TPEN rescues dopamine- and DHX-induced neuron death 61 Fig. 6. MCC950 suppresses dopamine and DHX-induced neuron death 63 Fig. 7. VX-765 suppresses dopamine and DHX-induced neuron death in cultured neurons 65 Fig. 8. TPEN suppresses DA-induced expression pyroptosis-related genes 67 Fig. 9. TPEN suppresses dopamine-increased expression pyroptosis-related genes by qPCR analysis in cultured neurons 69 Fig. 10. Dopamine enhances the expression of pyroptosis-related genes via Zn2+ 71 Fig. 11. TPEN suppressed dopamine-induced pyroptosis-related proteins level via D1-like receptor 73 Fig. 12. IL-1β pretreatment protects neurons from DA-induced cell death 75 Fig. 13. An illustration of the pyroptosis involvement of DA-induced elevation of [Zn2+]i via D1-like receptor 77 | |
dc.language.iso | en | |
dc.title | 探討鋅離子在多巴胺誘導對大鼠初代培養神經細胞焦亡中的影響 | zh_TW |
dc.title | Study the Effects of Zn2+ in Dopamine-induced Pyroptosis in Primary-cultured Rat Embryonic Cortical Neurons | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 李怡萱(Yi-Hsuan Lee),江皓森(Hao-Sen Chiang) | |
dc.subject.keyword | 多巴胺,炎症小體,神經退化性疾病,神經炎症,細胞焦亡,鋅離子, | zh_TW |
dc.subject.keyword | dopamine,inflammasome,neurodegeneration,neuroinflammation,pyroptosis,Zn2+, | en |
dc.relation.page | 77 | |
dc.identifier.doi | 10.6342/NTU202003034 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-08-14 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生命科學系 | zh_TW |
顯示於系所單位: | 生命科學系 |
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