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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林育誼(Yu-Yi Lin) | |
| dc.contributor.author | Ching-Yu Liu | en |
| dc.contributor.author | 劉晴語 | zh_TW |
| dc.date.accessioned | 2021-06-08T04:59:09Z | - |
| dc.date.copyright | 2011-10-05 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-19 | |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23320 | - |
| dc.description.abstract | 發生在生物體內一天中的各種規律變化，謂之日夜節律。哺乳動物的中央節律時鐘位處下視丘上視神經交叉核，負責驅動生物體的日夜節律、整合全身的生理與行為模式，如睡眠、能量衡定、周邊循環荷爾蒙濃度及新陳代謝等等。中央驅動日夜節律，可以自發性的產生，然而一些環境的線索，如光線、溫度等，也可以重置日夜節律。大多數哺乳動物的周邊組織例如肝臟等器官，也存在其日夜節律的時鐘，可以經由循環於血液的訊號，如荷爾蒙，達成與中央日夜節律時鐘同步的生理狀態。
從分子的角度來探討，日夜節律的現象是源自細胞中存在一個自動地轉錄與轉譯後回饋路徑，許多轉錄因子參與其中的核心部分，其表現量呈現日夜節律變化，因而使其下游調控的基因表現也呈現日夜節律的變化。其中一個下游的產出基因 ─ Nocturnin，是一個去腺嘧啶酶 (deadenylase)，會特異性的移除RNA polymerase II所驅動的轉錄子聚腺苷尾部 (poly (A) tails)，因此降低這些轉錄子的穩定性。先前研究指出，Nocturnin在許多組織中皆存在，尤其午夜時分時，在老鼠的肝臟有極高的表現量，而此基因會影響體內葡萄糖和脂質的代謝，雖然詳細機制目前尚未被完整研究。相關文獻報導指出，體內許多新陳代謝會呈現日夜節律的現象；此外，微型核醣核酸(microRNA)也被發現其參與日夜節律的調控。釐清這些詳細的分子機制有助於我們獲得更多的訊息，期望對於預防或治療代謝相關疾病能有更多突破性的進展。 此篇論文希望藉由比較野生型與Nocturnin基因剔除型老鼠，進而找到肝臟中會呈現日夜節律變化的微型核醣核酸，並研究Nocturnin對於微型核醣核酸穩定度的影響。在微陣列（microarray）與後續即時定量聚合酶連鎖反應分析中發現，miR-709在兩組老鼠中皆會呈現白天較午夜高的規律變化，顯示其可能參與調控生物體的日夜節律；此外，在 Nocturnin基因剔除型老鼠中，miR-690的表現量會明顯地升高，說明Nocturnin與miR-690之間存在有某些關連性。隨後我們利用北方墨點法來探討miR-709晝夜變化的現象是源自於轉錄或轉錄後的階段，結果顯示，miR-709的前驅物 (pri-miR-709與pre-miR-709) 在午夜時表現量皆有下降的現象，而pre-miR-709的變化量與表現量顯著較pri-miR-709為多; 另外，在北方墨點法中無法偵測到mature miR-709表現量的現象，可能意味著從pre- miR-709到mature miR-709的過程中存在一個非典型的調控機制。我們希望藉由解開這些謎團，能找到同時調控日夜節律與新陳代謝功能的轉錄後修飾機制，並期望有朝一日，能有助於代謝相關疾病的預防或治療。 | zh_TW |
| dc.description.abstract | Rhythms that occur regularly with a 24-hour periodicity are considered circadian. In mammalian species, circadian rhythms are regulated by a master pacemaker in the hypothalamic suprachiasmatic nucleus (SCN), which coordinates many physiological and behavioral processes such as sleep-wake cycles and metabolic functions. Peripheral clocks are also present in almost all mammalian tissues including liver, where they are synchronized by the central clock program by various circulating entraining factors to maintain circadian rhythms and modulate output pathways in a tissue-specific manner. At the molecular level, circadian rhythms are generated by interlocking transcriptional feedback loops and post-translational modifications of several “clock” proteins. Nocturnin is one of the downstream circadian output genes, which encodes an RNA deadenylase, involved in the regulation of glucose and lipid metabolism at the post-transcriptional level in multiple tissues, particularly in the liver. Many metabolic events have been shown to exhibit circadian oscillation, and previous studies also revealed miRNAs as important modulators of the circadian processes. Understanding the functional relationships between miRNA and complex metabolic pathway will gain more information to design new therapy strategies for metabolic disease.
In order to identify rhythmic miRNAs in mouse liver and examine the effect of Nocturnin knockout on miRNA stability, we performed miRNA microarray and validated the results by TaqMan qRT-PCR assay. Using this method we have confirmed the rhythmic expression pattern of miR-709 and Nocturnin-dependency of miR-690. miR-709 exhibits rhythmic expression in both wild-type (WT) and Nocturnin knockout (KO) mice, with particular high amplitude at ZT 0, suggesting its possible role in the regulation of circadian processes. miR-690 is significantly upregulated in Nocturnin KO mice at both time points, indicating a potential connection between Nocturnin and miR-690. To distinguish between transcriptional and/or post-transcriptional control for the mature miR-709 diurnal variations, we analyzed the expression levels of miR-709 precursor RNAs by Northern blot analysis. Both pri-miR-709 and pre-miR-709 increase at ZT 0, but the fold-change of pre-miR-709 is disproportionately more than that of pri-miR-709. In addition, mature miR-709 signal was surprisingly undetectable on the blot, compatible with an unusual processing mechanism of pre-miR-709 to mature miRNAs. By unraveling these puzzles, we expect to identify novel post-transcriptional mechanisms regulating circadian rhythm and the metabolic output in mammals. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T04:59:09Z (GMT). No. of bitstreams: 1 ntu-100-R98442029-1.pdf: 923033 bytes, checksum: a64ce9db240d55248474a06cd48dc286 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | Table of Contents
List of tables...........................................iii List of figures...........................................iv Abstract in Chinese........................................v Abstract..................................................vi Chapter 1 Introduction.....................................1 1.1 Crosstalk between circadian clock and cellular metabolism..............................................1 1.1.1 Circadian rhythm...................................1 1.1.2 Circadian clocks...................................2 1.1.2.1 The location of the mammalian biological clock..2 1.1.2.2 Current models of the mammalian molecular clocks3 1.1.3 The connection between circadian rhythms and metabolism.................................................5 1.1.4 Nocturnin in circadian clock and cellular metabolism.................................................8 1.2 The roles for miRNAs in the circadian clock and metabolism................................................11 1.2.1 Overview of miRNA................................11 1.2.2 General miRNA biogenesis and functions...........12 1.2.3 Roles of miRNAs in metabolism....................15 1.2.4 The interlock between circadian clocks and miRNAs16 1.3 Next-generation sequencing (NGS).....................19 1.4 Specific aims........................................21 Chapter 2 Materials and Methods...........................23 2.1 Total RNA isolation..................................23 2.2 miRNA microarray.....................................23 2.3 Small RNA library preparation (Illumina/Solexa)......24 2.4 TaqMan quantitative real-time PCR analysis...........25 2.5 Northern blotting....................................27 2.6 Statistical analysis.................................29 Chapter 3 Results.........................................30 3.1 Several miRNAs showing cyclic expression patterns in mouse liver...............................................30 3.2 Confirmation of array data by TaqMan quantitative real-time PCR..................................................31 3.3 miR-709 exhibits an unusual processing pattern observed by Northern blot.................................32 Chapter 4 Discussion......................................33 4.1 Low signal of mature miR-709 signals observed on Northern blot.............................................33 4.2 The possible crosslink between Nocturnin and miR-690.34 4.3 Potential mechanisms of miR-690 and miR-709 in the Regulation of circadian rhythms...........................35 Figures...................................................37 Tables....................................................41 References................................................44 | |
| dc.language.iso | en | |
| dc.subject | 肝臟代謝 | zh_TW |
| dc.subject | 日夜節律 | zh_TW |
| dc.subject | 微小核醣核酸 | zh_TW |
| dc.subject | 轉錄後調節 | zh_TW |
| dc.subject | circadian rhythm | en |
| dc.subject | metabolism | en |
| dc.subject | post-transcriptional regulation | en |
| dc.subject | microRNA | en |
| dc.title | 研究哺乳動物日夜節律之肝臟組織特異性轉錄後調節 | zh_TW |
| dc.title | Explore the liver-specific post-transcriptional regulation of circadian rhythm related to Nocturnin in mammals | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 莊立民,詹世鵬 | |
| dc.subject.keyword | 日夜節律,微小核醣核酸,轉錄後調節,肝臟代謝, | zh_TW |
| dc.subject.keyword | circadian rhythm,microRNA,post-transcriptional regulation,metabolism, | en |
| dc.relation.page | 54 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2011-08-19 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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