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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 潘建源 | zh_TW |
dc.contributor.advisor | Chien-Yuan Pan | en |
dc.contributor.author | 曾惠群 | zh_TW |
dc.contributor.author | Hui-Chiun Tseng | en |
dc.date.accessioned | 2024-03-21T16:23:58Z | - |
dc.date.available | 2024-03-22 | - |
dc.date.copyright | 2024-03-21 | - |
dc.date.issued | 2024 | - |
dc.date.submitted | 2024-02-01 | - |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92277 | - |
dc.description.abstract | 離子恆定參與調節許多重要生理功能,如鐵離子參與在氧氣的運輸,鈉鉀離子參與動作電位的變化,以及鈣離子調控神經傳遞物質的釋放和肌肉的收縮等等。而鋅離子常作為輔酶維持蛋白質與酵素的功能,同時也是許多蛋白據以維持結構的重要因子。近年研究發現有多種鋅離子轉運蛋白與結合蛋白,可嚴格調控細胞中鋅離子的恆定,而鋅離子恆定失調可導致細胞凋亡甚至神經退化等疾病。先前研究顯示,帕金森氏症患者腦中黑質的鋅離子濃度較健康者高,顯示高濃度的鋅離子可能對神經有害。然而帕金森氏症的研究,多集中於探討多巴胺 (dopamine, DA)氧化所產生活性氧類物質破壞粒線體,或是鋅離子影響粒線體功能,導致神經細胞死亡與神經退化;然而我們實驗室先前的研究成果顯示,DA會透過D1-like 受體活化NO合成酶 (NOS) 產生一氧化氮,提升胞內鋅離子濃度 ([Zn2+]i),以啟動細胞自嗜導致離體培養的大鼠胚胎皮質神經細胞死亡。而另一種常見的興奮性神經傳遞物質麩胺酸 (glutamate, Glu),已知也可活化NOS,但不知Glu是否亦可增加 [Zn2+]i。
近年研究發現,發炎反應是神經退化的原因之一。本研究中,我們首先使用D1-like 受體的促進劑 DHX,證實在初級培養的大鼠胚胎神經細胞中,並非DA的氧化,而是透過D1-like 受體造成 [Zn2+]i 上升,而發炎抑制劑可減少多巴胺鋅離子所造成的神經細胞死亡;且DA透過 [Zn2+]i 上升,增加NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)發炎小體的形成;除增加NLRP3的表現量,也使下游Caspase-1活化,導致interleukin-1 beta (IL-1β)及Gasdermin D (GSDMD)成熟。且分解後的N端GSDMD,並沒有到細胞膜,而主要是到自嗜小體上,當我們以IL-1β預處理神經細胞,可降低DA造成的神經細胞死亡。這些成果顯示輕微的發炎反應與神經細胞中細胞自嗜有交互作用,影響細胞存活。 而以Glu刺激培養的神經細胞,我們發現會透過離子型Glu受體,經由鈣離子,活化鈣調素/鈣調素依賴蛋白激酶 II ,短期增加NOS磷酸化,以合成NO,導致 [Zn2+]i 上升。且短時間內並不會破壞粒線體的活性,但卻增加了NLRP3發炎小體的數量,而Zn2+ 螯合劑,TPEN的預處理可抑制發炎小體的產生。因此維持鋅離子恆定,是防止神經細胞誘發發炎反應導致死亡的關鍵因素。 不同的神經傳導物質,利用各自的途徑,活化NOS產生NO,使 [Zn2+]i上升,以啟動細胞自嗜、發炎反應等機制,進行交互作用而導致細胞死亡。這些結果顯示神經傳導過程中,鋅離子是一個重要的訊息分子,調控神經細胞長期活性變化;因此了解如何控制鋅離子恆定以調節自嗜及發炎,可為神經退化性疾病的治療,提供新穎的發展策略。 | zh_TW |
dc.description.abstract | Ion homeostasis is involved in many critical physiological functions. For instance, iron participates in oxygen transport, sodium and potassium modulate the action potentials in neurons, and Ca2+ regulates neurotransmitter release and muscle contraction. Zinc ion (Zn2+) serve as co-factors to maintain the functions and structures of proteins and enzymes. Recent studies have discovered multiple Zn2+ transporters and binding proteins that strictly regulate the steady-state of the intracellular Zn2+ concentration ([Zn2+]i) within cells. Disruption in Zn2+ homeostasis has been linked to cell apoptosis and neurodegenerative diseases. Some studies have shown higher Zn2+ level in the substantia nigra of Parkinson''s disease (PD) patients compared to healthy individuals, indicating that elevated Zn2+ might be detrimental to neurons. However, PD research has primarily focused on investigating dopamine (DA) oxidation, resulting in the generation of reactive oxygen species that damage mitochondria and lead to neuronal cell death; there is limited research that focuses on the impact of Zn2+ homeostasis on neurodegeneration.
Our previous studies have indicated that DA through the activation of D1-like receptors, induces nitric oxide synthase (NOS) to produce nitric oxide (NO), leading to increase in intracellular Zn2+ concentration ([Zn2+]i). This increment triggers autophagy, ultimately resulting in the death of primary cultured rat embryonic cortical neurons. Another common excitatory neurotransmitter, glutamate (Glu), is also known to activate NOS, but it remains unclear whether Glu increases [Zn2+]i for signaling pathway activation. Recent research has highlighted the role of inflammation as one of the factors contributing to neurodegeneration. In this study, we initially used the D1-like receptor chemically stable agonist, dihydrexidine (DHX), confirming in primary cultured rat embryonic neurons that the increase in [Zn2+]i was not due to DA oxidation but rather through D1-like receptor stimulation. Additionally, inhibition of inflammation reduced DA-Zn2+-induced neuronal cell death. Furthermore, the elevation of [Zn2+]i by DA increased the formation of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasomes and activated downstream Caspase-1, leading to the maturation of interleukin-1 beta (IL-1β) and Gasdermin D (GSDMD). Notably, the cleaved N-terminal of GSDMD did not translocate to the cell membrane but was primarily observed in autophagosomes. Pretreatment of neurons with IL-1β reduced DA-induced neuronal cell death, suggesting that mild inflammation and its interaction with autophagy account for neuron death. Regarding Glu-stimulated cultured neurons, we observed that Glu activated NOS through ionotropic Glu receptors, leading to transient phosphorylation and subsequent synthesis of NO via the Ca2+-CaM/CaMKII pathway, causing an increase in [Zn2+]i. While this short-term increase did not impact mitochondrial activity, it elevates the expression level of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasomes. Pretreatment with the Zn2+ chelator, TPEN, inhibited inflammasome formation. Hence, maintaining Zn2+ homeostasis is crucial in preventing inflammatory responses induced in neurons. These results demonstrate that different neurotransmitters, through their respective pathways, activate NOS to generate NO, resulting in [Zn2+]i elevation and triggering mechanisms such as autophagy and inflammatory responses, ultimately leading to cell death. After neurotransmitters activate the electrical and Ca2+ responses, Zn2+ can then be a novel signaling molecule during neurotransmission to regulate the long-term activities of neurons. Therefore, understanding how to control Zn2+ homeostasis to regulate autophagy and inflammation could offer novel strategies for treating neurodegenerative diseases. | en |
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dc.description.tableofcontents | 誌謝 i
中文摘要 ii Abstract iv Abbreviations vii 1. INTRODUCTION 1 1.1 The physiological functions of the Zn2+ 1 1.2 Zn2+ homeostasis 3 1.3 Zn2+ in the neurodegenerative diseases 5 1.4 Neurotransmitters 7 1.4.1 Dopamine 8 1.4.2 Glutamate 9 1.4.3 Histamine 12 1.4.4 Acetylcholine 16 1.5 Neuroinflammation and pyroptosis 17 1.6 Autophagy 20 1.7 Interplay between inflammatory response and autophagy 23 1.8 Aims 24 2. MATERIALS AND METHODS 26 2.1 Chemicals 26 2.2 Primary culture of rat embryonic cortical neurons 26 2.3 Drugs treatments 28 2.4 Ion imaging 29 2.5 NO imaging 31 2.6 MTT assay 31 2.7 Western blot analysis 32 2.8 Immunocytofluorescence (ICF) 33 2.9 Enzyme-linked immunosorbent assay 34 2.10 Data analysis 34 3. RESULTS 36 3.1 DHX induce-[Zn2+]i elevation in a dose-dependent manner in neurons 36 3.2 TPEN inhibits DHX-induced [Zn2+]i enhancement 36 3.3 DHX-induced neuron death is dose-dependent 37 3.4 TPEN rescues DHX-induced cell death in cultured neurons 38 3.5 Short-term DA or DHX treatment does not affect viability in neurons 38 3.6 Inflammation antagonist against DA or DHX-induced neuron death 39 3.7 Short-term DA or DHX treatment increases NLRP3 expression level 40 3.8 Long-term DA or DHX treatment does not enhance NLRP3 levels in cultured neurons 41 3.9 DA and DHX enhance the expression of inflammation-related proteins in cultured neurons 41 3.10 DA does not translocate N-GSDMD to the neuronal plasma membrane 43 3.11 DA induces colocalization of N-GSDMD and autophagosomes in neurons 44 3.12 DA does not induce mature IL-1β secretion in primary cultured neurons 44 3.13 IL‑1β provides neuroprotection against DA-induced cell death 45 3.14 Glu elevates [Zn2+]i in a dose-dependent manner in cultured neurons 46 3.15 TPEN suppresses Glu-induced elevation of [Zn2+]i in cultured neurons 46 3.16 Agonists of iGluR elevate [Zn2+]i in cultured neurons 47 3.17 Antagonists of iGluR inhibits the Glu-induced Zn2+ response 48 3.18 Agonists of iGluR elevate [Ca2+]i in cultured neurons 48 3.19 mGluR agonist does no effect on the [Zn2+]i in cultured neurons 49 3.20 Agonist of group I mGlR elevates the [Ca2+]i in cultured neurons 50 3.21 W7 and KN62 inhibit the Glu-induced intracellular Zn2+ 50 3.22 NIO and L-NPA inhibit Glu-induced Zn2+ generation 51 3.23 Agonists of iGluR elevate [NO]i in cultured cortical neurons 51 3.24 TPEN does not suppress Glu-induced NO generation 52 3.25 W7 and KN62 suppress Glu-induced NO production in neurons 52 3.26 Inhibitors of NOS block Glu-induced NO generation in neurons 53 3.27 Membrane depolarization elevates the [Ca2+]i in cultured neurons 53 3.28 Depolarization-evoked Ca2+ response does not induce NO generation in cultured neurons 54 3.29 Membrane depolarization could not elevate [Zn2+]i in cultured neurons 55 3.30 Glu transiently increases the phosphorylation level of the nNOS at Ser847 or at Ser1417 in neurons 55 3.31 Glu-induced NLRP3 inflammasome formation 56 3.32 Short-term Glu treatment did not affect mitochondrial activity 57 4. DISCUSSIONS 58 4.1 DA and Glu differentially interfere with the Zn2+ homeostasis in neurons 58 4.2 Inflammation participates in DA-induced neuron death 59 4.3 The physiological increase in [Zn2+]i triggers the inflammatory response 60 4.4 DA transiently activates the inflammatory response 61 4.5 DA-triggered localization of N-GSDMD to the autophagosomes 61 4.6 IL-1β pretreatment rescue DA or DHX-induced neuron death 63 4.7 Glu induced [Zn2+]i elevation via iGluR but not mGluR 64 4.8 Glu-induced NO generation is upstream of the [Zn2+]i elevation 66 4.9 Receptor-mediated activation of CaMKII and NOS activation 66 4.10 Glu-activated inflammation is Zn2+-dependent 68 5. CONCLUSIONS 70 6. REFERENCE 73 7. FIGURES 105 Fig. 1 DHX-induces [Zn2+]i elevation in a dose-dependent manner 107 Fig.2 TPEN effectively attenuates DHX-induced [Zn2+]i in cultured neurons 109 Fig. 3 The dose-dependent effect of DHX on neuron death 111 Fig. 4 TPEN rescues DHX-induced neuron death 113 Fig.5 Short-term DA or DHX treatment does not induce neuron death 115 Fig. 6 Antagonists of inflammation against DA or DHX-induced neuron death. 117 Fig. 7 DA or DHX treatment increases cytosolic NLRP3 expression level. 119 Fig. 8 Lon-term DA or DHX treatment does not increase cytosolic NLRP3 expression in neurons. 121 Fig. 9 DA or DHX upregulate inflammation-related protein expression in cultured cortical neurons via D1R-Zn2+ signaling cascade. 123 Fig. 10 DA does not induce N-GSDMD translocation to the neuronal plasma membrane. 125 Fig. 11 DA-induced N-GSDMD translocates to the autophagosomes. 127 Fig. 12 DA treatment did not release mature IL-1β in cultured neurons. 129 Fig. 13 IL-1β pretreatment against DA or DHX-induced neuron death. 131 Fig. 14 Glu-induced Zn2+ elevation is a dose-dependent response in neurons. 133 Fig. 15 TPEN suppresses Glu-induced [Zn2+]i elevation. 135 Fig. 16 iGluR activation induces [Zn2+]i elevation in cultured neurons. 137 Fig. 17 iGluR antagonists inhibit Glu-induced [Zn2+]i elevation. 139 Fig. 18 Agonist of iGluR increases intracellular Ca2+ levels. 141 Fig. 19 mGluR agonist induces [Zn2+]i elevation in cultured neurons. 143 Fig. 20 mGluR agonist induces elevation in [Ca2+]i. 145 Fig. 21 W7 and KN62 suppress Glu-induced [Zn2+]i elevation in neurons. 147 Fig. 22 NIO and L-NPA inhibit Glu-induced [Zn2+]i elevation in neurons. 149 Fig. 23 iGluR agonist-induced NO generation in cultured cortical neurons. 151 Fig. 24 Tsuppressot suppresses Glu-induced NO elevation in neurons. 153 Fig. 25 W7 and KN62 inhibit Glu-induced [NO]i elevation in neurons. 155 Fig. 27 Neuronal depolarization elicits Ca2+ influx. 159 Fig. 28 Ca2+ influx failed to induce NO generation in cultured neurons. 161 Fig. 29 Neuronal depolarization does not induce [Zn2+]i elevation. 163 Fig. 30 Glu triggers nNOS phosphorylation at Ser1417 in cultured neurons. 165 Fig. 31 TPEN reduces Glu-induced cytosolic NLRP3 expression in neurons. 167 Fig. 32 Short-term Glu treatments do not affect mitochondrial activity. 169 Fig. 33 An illustration of the mechanism of neurotransmitter DA- and Glu-induced [Zn2+]i elevation and inflammatory response. 171 | - |
dc.language.iso | zh_TW | - |
dc.title | 神經傳遞物質增加胞內鋅離子濃度與神經發炎反應在初代培養大鼠神經細胞的關聯 | zh_TW |
dc.title | Investigation into Neurotransmitter-Induced Intracellular Zn2+ Elevation and its Correlation with Inflammatory Response in Primary-Cultured Rat Embryonic Cortical Neurons | en |
dc.type | Thesis | - |
dc.date.schoolyear | 112-1 | - |
dc.description.degree | 博士 | - |
dc.contributor.oralexamcommittee | 李怡萱;吳姿樺;陳儀莊;廖永豐;江皓森 | zh_TW |
dc.contributor.oralexamcommittee | Yi-Hsuan Lee;Tzu-Hua Wu;Yijuang Chern;Yung-Feng Liao;Hao-Sen Chiang | en |
dc.subject.keyword | 多巴胺,麩胺酸,發炎反應,神經退化性疾病,一氧化氮,一氧化氮合成酶,鋅離子, | zh_TW |
dc.subject.keyword | dopamine,glutamate,inflammatory response,neurodegeneration,nitric oxide,nitric oxide synthase,Zn2+, | en |
dc.relation.page | 171 | - |
dc.identifier.doi | 10.6342/NTU202400419 | - |
dc.rights.note | 未授權 | - |
dc.date.accepted | 2024-02-05 | - |
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 |
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