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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 孟子青(Tzu-Ching Meng) | |
dc.contributor.author | Yen-Jung Chen | en |
dc.contributor.author | 陳彥蓉 | zh_TW |
dc.date.accessioned | 2021-06-17T03:28:06Z | - |
dc.date.available | 2021-04-18 | |
dc.date.copyright | 2018-04-18 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-03-26 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69791 | - |
dc.description.abstract | 神經細胞間協調去執行大腦功能是耗氧的過程。因此,由慢性阻塞性肺病引起的慢性缺氧導致神經損傷並不令人驚訝。當皮質出現損傷時,會出現焦慮和認知功能障礙,從而促進神經退化性疾病的發展。迄今為止,低氧所引發之神經損傷的潛在機制仍然是未知並難以捉摸的。在本研究中,我們已經證明在N2a細胞和皮質神經元暴露於缺氧所引發的神經退化是由caspase-6主導。缺氧導致caspase-6去亞硝基化而活化,而經由亞硝酸鹽的處理可減緩缺氧對神經細胞的不利影響,顯示在低氧環境下亞硝酸鹽的作用可以使caspase-6失活的可能。隨後的生物素轉換法顯示了caspase-6的活化位點Cys146在亞硝酸鹽供應的缺氧神經元中被亞硝基化。使用暴露於慢性缺氧的Apo E基因剔除小鼠作為模型,我們進一步證明了飲用水中添加亞硝酸鹽可以抑制大腦皮質中的活化的caspase-6,並防止由缺氧所引起的焦慮。這些實驗結果顯示了caspase-6活化的新途徑與亞硝酸鹽可以減緩缺氧所引發的神經損傷。我們的研究結果也表明了亞硝酸鹽具有治療缺氧所引發之神經損傷相關疾病的巨大潛力。 | zh_TW |
dc.description.abstract | Coordination of neurons that executes brain functions is an oxygen-demanding process. It is thus not surprising that chronic hypoxia caused by chronic obstructive pulmonary diseases leads to neuronal damages. When the injury occurs in cortex, anxiety and cognitive dysfunction may appear, consequently promoting the development of neurodegenerative disorders. To date, the underlying mechanism of hypoxia-induced neuronal injury remains elusive. In this study, we have demonstrated that exposure of N2a cells and cortical neurons to hypoxia resulted in neurite degeneration, which is a caspase-6-dependent process. Hypoxia induces caspase-6 denitrosylation and activation. The detrimental effect of hypoxia on neurons was alleviated by nitrite treatment, suggesting a possible effect of nitrite on inactivation of caspase-6 under the hypoxic stress. The biotin-switch method subsequently depicted that the active-site Cys146 of caspase-6 was S-nitrosylated in hypoxic neurons supplied with nitrite. Using Apo E-/- mice exposed to chronic hypoxia as a model, we further demonstrated that nitrite supplement in drinking water suppressed active caspase-6 in the cortex of the brain, concomitant with the prevention of animals from hypoxia-induced anxiety. Collectively these results are the first to highlight a new pathway of caspase-6 activation and the protective role of nitrite in neurons against hypoxic insult. Our findings also suggest that nitrite holds a great potential for the treatment of diseases associated with hypoxia-induced neuronal injury. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T03:28:06Z (GMT). No. of bitstreams: 1 ntu-107-F00b46019-1.pdf: 12737243 bytes, checksum: a9d78c2d46546f24582c0e2366a207ef (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | TABLE OF CONTENTS
誌謝…………………….…………………………………………….………………....i 中文摘要……………………………………………………………………………....ii ABSTRACT……………………………………………………………………………iii ABBREVIATION…………………………………………………...…………………iv TABLE OF CONTENTS…………………………………………...…………………v CHAPTER 1: INTRODUCTION…………………………...………….1 1.1 Neuronal hypoxia in chronic obstructive pulmonary disease (COPD)…...…….2 1.2 Mechanisms of axon degeneration……………………...……………………….3 1.3 Caspase-6 S-nitrosylation and its role in regulating enzyme activity…………….4 1.4 Nitrite-Nitric oxide (NO) conversion and its application on neuronal damages…5 1.5 Focuses of this study…………………………………………...……………………6 CHAPTER 2: MATERIALS AND METHODS…………………….….9 2.1 Cell culture and hypoxia……………………………………...…………………...10 2.1.1 N2a cell culture and neurite outgrowth………………………………………10 2.1.2 Primary cell culture……………………………………...………………..10 2.1.3 Cell hypoxic treatment……………………………………...……………….11 2.1.4 Measurement of neurite length and statistical analysis ………...………….12 2.1.5 Cell transfection……………………………………...………………….......12 2.2 Apoptosis assay……………………………………...…………………………….13 2.3 Immunoblotting……………………………………...……………………………13 2.4 Immunofluorescence staining……………………………………...………….14 2.5 FLICA, Fluorescent-Labeled Inhibitor of Caspases…………………………….14 2.6 Detection of caspase-6 S-nitrosylation……………………………………...…….15 2.6.1 The biotin-switch method (BSM) ……………………………………...……15 2.6.2 MS analysis for caspase-6 S-nitrosylation……………………………….16 2.7 Animal experiments………………………………...………………………….17 2.7.1 Animal and hypoxic exposure………………………………...……………17 2.7.2 Blood chemistry. ………………………………...………………………….18 2.7.3 Open field………………………………...………………………………….18 2.7.4 Blood pressure measurement………………………………...……………...18 2.8 Statistics………………………………...……………………………………...….19 2.9 Reagents………………………………...……………………………………...19 CHAPTER 3: RESULTS AND DISCUSSION………………...…….20 3.1 Hypoxia induces neurite retraction but not overall apoptosis in N2a cell……21 3.2 Hypoxia induces neurite traction and caspase-6 activation in N2a cells…….22 3.3 Caspase-6 inhibition prevents hypoxia-induced neurite retraction…………….24 3.4 De-nitrosylation and activation of caspase-6 regulates hypoxia-induced neurite retraction…………………………………...……………………………………...26 3.5 Nitrite induces S-nitrosylation and inhibition of caspase-6 activity as well as neurite retraction under hypoxia………………………………...……………….27 3.6 Nitrite-derived NO targets to active-site Cys146 of transfected caspase-6 in N2a cells under hypoxia………………………………...………………………………29 3.7 Nitrite inhibits hypoxia-induced neurite retraction through XOR, eNOS and nNOS-dependent function………………………………...………………………32 3.8 The potential substrate of caspase-6 in neuronal cells that exposed to hypoxia...33 3.9 Inhibition of caspase-6 protects cortical neurons from hypoxia-induced neurite retraction……………………………...……………………………………………….36 3.10 Caspase-6 is activated within the neurites of cortical neurons exposed to hypoxia……………………………...………………………………………………….37 3.11 Nitrite protects cortical neurons from hypoxia-induced neurite degeneration.38 3.12 Hypoxia-induces anxiety in wild-type mice is partially suppressed by nitrite...40 3.13 Nitrite attenuates hypoxia-induced anxiety in an Apo E-/- mouse model………42 3.14 Discussion………………………………...………………………………………45 CHAPTER 4: SUMMARY AND FUTURE STUDIES…………...……52 4.1 Summary………………………………...………………………………………...53 4.2 Future studies………………………………...……………………………………55 CHAPTER 5: FIGURES…………………...……………………………………57 CHAPTER 6: REFERENCES…………………...…………………………….89 | |
dc.language.iso | en | |
dc.title | 亞硝酸鹽減緩缺氧引發之神經損害 | zh_TW |
dc.title | Nitrite protects neurons against hypoxic damage | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 張震東(Geen-Dong Chang),陳光超(Guang-Chao Chen),陳佩燁(Rita P.-Y. Chen),陳志成(Chih-Cheng Chen),姚季光(Chi-Kuang Yao) | |
dc.subject.keyword | 慢性阻塞性肺病,缺氧,半胱氨酸蛋白?-6,亞硝基化,亞硝酸鹽, | zh_TW |
dc.subject.keyword | COPD,hypoxia,caspase-6,S-nitrosylation,nitrite, | en |
dc.relation.page | 98 | |
dc.identifier.doi | 10.6342/NTU201800696 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-03-26 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
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ntu-107-1.pdf 目前未授權公開取用 | 12.44 MB | Adobe PDF |
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