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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蘇剛毅 | |
| dc.contributor.author | Wen-Hsin Li | en |
| dc.contributor.author | 李玟昕 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:07:32Z | - |
| dc.date.available | 2024-08-28 | |
| dc.date.copyright | 2019-08-28 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-08-13 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78616 | - |
| dc.description.abstract | 生理時鐘為調控代謝的重要機制，分為中央及器官周遭生理時鐘。在肝臟中，若週期紊亂會造成脂肪肝等代謝疾病。粒線體同為維持生理運作的中樞，過去研究指出粒線體形態的動態平衡會受到生理時鐘的調節。實驗室過去在人類肝臟熱休克蛋白40相似蛋白(HLJ1)的研究中發現HLJ1基因剔除(HLJ1-/-)小鼠肝臟有脂肪生成和代謝異常的現象，且在正常(WT)及HLJ1-/-小鼠肝臟RNA微陣列結果分析發現生理時鐘相關基因路徑有顯著差異。故本篇研究欲探討HLJ1在生理時鐘調控脂肪代謝的關係及對粒線體形態的影響。RNA微陣列路徑分析顯示HLJ1與生理時鐘高度相關。欲進一步探討兩者的相關性，我們使用小鼠胚胎成纖維細胞（MEF）及小鼠的肝細胞(hepatocyte)，並利用地塞米松(dexamethasone)同步細胞生理時鐘。細胞實驗顯示生理時鐘相關基因確實呈現週期震盪，但WT及HLJ1-/-組別只有部分時間點有差異，整體沒有顯著差異，在小鼠肝臟實驗也獲得相同結果。在研究脂肪代謝的實驗中，結果顯示小鼠血清中三酸甘油酯與總膽固醇也會隨時間產生週期，且兩組在相位與量上都有差異。但在脂肪代謝相關基因與蛋白表現量中，兩組並無差異。我們發現HLJ1在細胞中週期不規律但在肝臟中不管基因還是蛋白層面都有明顯週期的變化。接著，我們利用西方墨點法及免疫螢光染色探討影響線粒體形態，結果可見融合/裂變蛋白表達及和螢光圖中的粒線體形態會受到羰基氰化物間氯苯腙(CCCP)而形成分裂態，但在WT及HLJ1-/- MEF沒有顯著差異。最後，為了更清楚的觀察粒線體形態，我們建立一株粒線體會自發螢光的NIH3T3細胞，可用於進一步研究粒線體形態。 | zh_TW |
| dc.description.abstract | Circadian clock is the organizer of body biological functions, the disruption of clock in liver causes metabolic diseases such as fatty liver. Mitochondrial morphological change is also a critical mechanism that involves in many metabolic processes, researches have indicated that the dynamic balance of mitochondrial morphology is regulated by circadian clocks. Study of HLJ1 in our lab has found that HLJ1 knockout (HLJ1-/-) mice had abnormalities in lipogenesis and metabolism in liver. We wonder to know the relationship between HLJ1, circadian rhythms and mitochondria dynamic. We utilized mouse embryonic fibroblast (MEF) and hepatocyte from wild-type (WT) and HLJ1-/- mice for experiments. The results displayed the expression levels of circadian related genes were oscillated, but there were no significant difference between those two groups. The same results were seen in liver of WT and HLJ1-/- mice. The results of lipid metabolism of mice showed that triglyceride and total cholesterol in serum also produced rhythmicity by time, the phase and amount were different in two groups. However, there was no difference between the two groups in lipid metabolism related genes and proteins in liver. In addition, the duration pattern of HLJ1 was significant in mRNA and protein level in liver compared to the cell experiments. In the study of mitochondrial morphology, there was no difference in fusion/fission proteins expression and images of immunofluorescence staining of WT and HLJ1-/- MEF. Finally, we generated auto-fluorescent mitochondria in NIH3T3 that could be used for further investigation of mitochondrial morphology. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:07:32Z (GMT). No. of bitstreams: 1 ntu-108-R06424001-1.pdf: 6347950 bytes, checksum: d2ddb0cbab262a1b9b3f416ec045c986 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 口試委員會審訂書 #
誌謝 i 中文摘要 iii ABSTRACT iv ABBREVIATIONS vi Chapter 1 Introduction 1 1.1 Circadian rhythms 2 1.2 Circadian rhythms and liver metabolism 3 1.3 Heats shock proteins (HSPs) and HLJ1 4 1.4 Mitochondria and Disease 5 1.5 Mitochondrial morphology dynamics 6 1.6 Circadian rhythms and mitochondria 7 1.7 Specific aims 8 Chapter 2 Materials and Methods 9 2.1 Experimental Animals 10 2.2 cDNA Microarray analysis 10 2.3 Cell lines 10 2.4 Drug treatment 11 2.5 RNA extraction and Quantitative RT-PCR analysis 12 2.6 Protein extraction and Western blotting analysis 14 2.7 Lipid analysis 15 2.8 Immunofluorescence staining 16 2.9 NIH3T3 fluorescent labeled mitochondria stable clone 17 2.9.1 Transformation 17 2.9.2 Plasmid extraction 17 2.9.3 Restriction enzyme confirmation 18 2.9.4 Transfection 19 2.9.5 Stable clone selection 19 2.10 High content screening 20 2.11 Statistical analysis 20 Chapter 3 Results 21 3.1 Circadian rhythm related genes are differently expressed in liver of wild-type and HLJ1 knockout mice 22 3.2 The difference of circadian rhythm related genes between wild-type and HLJ1 knockout MEF cells was in time points but not in duration patterns 22 3.3 The period fluctuation of circadian rhythm related genes were not obvious in both wild-type and HLJ1 knockout hepatocytes 24 3.4 The oscillation of circadian related genes in livers of HLJ1 knockout mice showed no significant difference with wild-type mice 25 3.5 Deletion of HLJ1 altered the diurnal patterns of hepatic lipid metabolism 26 3.6 The mitochondrial morphological changed between MEF wild-type and HLJ1 knockout cells 27 3.7 Establishment of mitochondrial morphology analysis using NIH3T3 and high content screening 29 Chapter 4 Discussion 31 4.1 The alternation of circadian rhythms without HLJ1 in MEF cells 32 4.2 The alternation of circadian rhythms without HLJ1 in hepatocyte 33 4.3 The alternation of circadian rhythms and lipid metabolism in liver without HLJ1 34 4.4 The relationship between mitochondrial morphological change and HLJ1 35 4.5 The limitation of analyzing the mitochondrial morphology 36 Chapter 5 Conclusion 38 Chapter 6 Tables 40 Table 1. Primer sequences used in quantitative RT-PCR 41 Chapter 7 Figures 42 Figure 1. cDNA microarray analysis to explore HLJ1-associated biological pathway in circadian rhythms. 45 Figure 2. Gene expression levels of circadian rhythms related genes in wild-type and HLJ1-/- MEF. 49 Figure 3. Gene expression levels of circadian rhythms related genes in wild-type and HLJ1-/- hepatocyte. 51 Figure 4. Gene expression levels of circadian rhythms related genes in wild-type and HLJ1-/- mice livers. 54 Figure 5. Lipid metabolism in liver of wild-type and HLJ1-/- mice. 59 Figure 6. Mitochondrial morphology of wild-type and HLJ1-/- MEF. 63 Figure 7. NIH3T3 with autofluorescent mitochondria. 66 REFERENCES 67 | |
| dc.language.iso | en | |
| dc.title | 探討HLJ1透過影響生理時鐘調控代謝及粒線體形態變化所扮演之角色 | zh_TW |
| dc.title | The role of HLJ1 to regulate metabolism and mitochondria morphological change via circadian rhythms modulation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林亮音,楊雅倩,郭靜穎 | |
| dc.subject.keyword | 生理時鐘,人類肝臟熱休克蛋白40相似蛋白,粒線體形態,脂肪代謝,自發螢光粒線體,多參數細胞影像分析儀, | zh_TW |
| dc.subject.keyword | circadian rhythms/clocks,HLJ1,mitochondrial dynamic,lipid metabolism,auto-fluorescent mitochondria,high content screening, | en |
| dc.relation.page | 76 | |
| dc.identifier.doi | 10.6342/NTU201903458 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-08-13 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| dc.date.embargo-lift | 2024-08-28 | - |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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