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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 莊立民(Lee-Ming Chuang) | |
| dc.contributor.author | Chien-Jung Guo | en |
| dc.contributor.author | 郭千榕 | zh_TW |
| dc.date.accessioned | 2021-06-17T01:55:43Z | - |
| dc.date.available | 2019-09-12 | |
| dc.date.copyright | 2017-09-12 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-07-21 | |
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Yasushi Fukushima, Hiraku Ono, Midori Fujishiro, Masatoshi Kikuchi, Yoshitomo Oka,, and a.T. Asano, Dexamethasone-Induced Insulin Resistance in 3T3-L1 Adipocytes Is Due to Inhibition of Glucose Transport Rather Than Insulin Signal Transduction. Diabetes, 2000. 49: p. 1700-1708. 23. Wiper-Bergeron, N., et al., Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPbeta by GCN5. Proc Natl Acad Sci U S A, 2007. 104(8): p. 2703-8. 24. Tomlinson, J.J., et al., Modulation of Early Human Preadipocyte Differentiation by Glucocorticoids. Endocrinology, 2006. 147(11): p. 5284-5293. 25. Cvoro, A., et al., Cross talk between glucocorticoid and estrogen receptors occurs at a subset of proinflammatory genes. J Immunol, 2011. 186(7): p. 4354-60. 26. Reddy, T.E., et al., Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. Genome Res, 2009. 19(12): p. 2163-71. 27. Frojdo, S., H. Vidal, and L. Pirola, Alterations of insulin signaling in type 2 diabetes: a review of the current evidence from humans. Biochim Biophys Acta, 2009. 1792(2): p. 83-92. 28. Dai, Q., et al., The BEN domain is a novel sequence-specific DNA-binding domain conserved in neural transcriptional repressors. Genes Dev, 2013. 27(6): p. 602-14. 29. Osathanon, T., et al., Notch signalling inhibits the adipogenic differentiation of single-cell-derived mesenchymal stem cell clones isolated from human adipose tissue. Cell Biol Int, 2012. 36(12): p. 1161-70. 30. Wang, Y. and H.S. Sul, Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9. Cell Metab, 2009. 9(3): p. 287-302. 31. Steven P. Weinstein, T.P., Alia Pritsker, and Richard S. Haber, Glucocorticoid-Induced Insulin Resistance: Dexamethasone Inhibits the Activation of Glucose Transport in Rat Skeletal Muscle by Both Insulin- and Non-Insulin-Related Stimuli. DIABETES, 1995. 44: p. 441-445. 32. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67880 | - |
| dc.description.abstract | 脂肪細胞的分化是非常細膩、複雜的過程。受到眾多的訊息路徑的嚴密調控。本實驗室之前經由差異呈現法篩選出一個在脂肪細胞分化過程中高度表現的基因，即前列腺素還原酶 2 (Prostaglandin reductase 2，簡稱為 PTGR2)，PTGR2 可將 15-keto-PGE2 代謝成 13,14-dihydro-15- keto-PGE2。在先前的研究中發現，PTGR2 參與脂肪細胞的分化，此外，我們也發現在糖尿病模式鼠中的臟器脂肪細胞 PTGR2
有大量之表現。但 PTGR2 的調控之分子機制仍未明瞭，因此本篇論文藉由脂肪細胞分化過程來探討 PTGR2 基因之表現如何被調控。我們從啟動子中被不同藥物和不同訊息路徑抑制劑的研究中發現，PTGR2 可透過 Dexamethasone-glucocorticoidreceptor (GR) 的路徑而被調控。經由轉錄因子結合位的軟體預測中，我們發現在PTGR2 啟動子上可能的 GR 結合位置，再藉由點突變 GR 的結合位置，並測量啟動子的活性實驗，我們得知在-277/-283 的結合位置對 PTGR2 啟動子活性上升很重要。我們再以 chromatin immunoprecipitation (ChIP)的實驗，證明在脂肪細胞分化過程中的確有 GR 結合在 PTGR2 的啟動子上，證實了 GR 對 PTGR2 轉錄調節的分子機制。另外，我們也探討 PTGR2 在生物體內是否有受到 GR 調控的現象，我們發現在正常 B57CL/6 老鼠連續注射大量 dexamethasone 三天後，發現 PTGR2 在腹股溝的脂肪組織有顯著上升，透過老鼠和細胞的兩種不同的實驗模式，我們證明PTGR2 如何被 Dexamethasone-GR 的路徑調控的機制。 | zh_TW |
| dc.description.abstract | Adipocyte differentiation is an elegant, complicated process involving sequentially activation of thousands of transcriptional factors. Our group previously discovered a novel enzyme, called prostaglandin reductase 2 (PTGR2) through mRNA differential display. PTGR2 is an oxidoreductase which catalyze 15-keto PGE2 to 13,14-dihydro-15-keto PGE2 as final product. In functional study, overexpression PTGR2 rather than its catalytic mutant inhibited adipocyte differentiation and relatively triacylglycerol content,which suggest a role of PTGR2 in adipogenesis. Additionally, PTGR2 is upregulated in omental fat in obese mouse model. However, the molecular mechanism of PTGR2 expression remains unknown. Results from promoter assay and inhibitors of different signaling pathways indicated that PTGR2 transcriptional regulation is possibly mediated via dexamethasone-GR pathway. Moreover, the predicted TF binding sites also indicated
presence of GR binding sites on PTGR2 promoter. With site-direct mutagenesis, we confirmed the proximal GR binding site at -277/-283 is responsible for promoter activation by dexamethasone. We then performed chromatin immunoprecipitation (ChIP) and demonstrated a direct binding of GR on PTGR2 promoter site. To further investigate the regulation of PTGR2 in vivo, we discovered that dexamethasone pulse therapy significantly upregulate PTGR2 mRNA in in inguinal fat tissue. Our findings thus support the dexamethasone-GR pathway that leads to PTGR2 activation in both cell and animal models. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T01:55:43Z (GMT). No. of bitstreams: 1 ntu-106-R02448010-1.pdf: 1492493 bytes, checksum: b368a01dc5c01d5de3b534bd28704455 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | Index
中文摘要III Abstract IV List of Tables IX Abbreviation X 1. Introduction 1 1.1 PTGR2 in adipogenesis and metabolism 1 1.1.1 Molecular mechanism of adipocyte differentiation 1 1.1.2 Prostaglandins (PGs) 2 1.1.3 PG and Adipogenesis 3 1.1.4 PGs and PPAR-γ 4 1.1.5 PTGR2 discovery and enzyme specificity 5 1.1.6 15-keto-PGE2 and PPAR-γ 6 1.1.7 PTGR2 and adipogenesis 6 1.1.8 PTGR2 and cancers 7 1.2 Glucocorticoid receptor 8 1.2.1 Glucocorticoids 8 1.2.2 Glucocorticoids and central obesity 8 1.2.3 Glucocorticoids and insulin resistance 9 1.2.4 Glucocorticoid and adipocyte differentiation 10 1.2.5 TypeⅡGlucocorticoid receptor (GR) 10 1.3 Motivation 11 2. Material and Method 13 2.1 Reagent 13 2.2 Cell culture 13 2.3 preparation of whole cell extraction 14 2.4 Western blot analysis 14 2.5 Total RNA extraction and Reverse-transcription quantitative PCR (RT-PCR) 15 2.6 Site-direct mutagenesis of mouse GRE on PTGR2 promoter 15 2.7 Promoter assay 16 2.8 Chromatin immunoprecipitation (ChIP) 16 2.9 Dexamethasone treatment 18 3. Results 19 3.1 PTGR2 is upregulated in 3T3-L1 cells during differentiation 19 3.2 PTGR2 promoter activity increases after induction of differentiation 19 3.3 Promoter deletion assay shows repressor activity on PTGR2 promoter 20 3.4 Differentiation cocktail component differentially regulate PTGR2 protein expression 20 3.5 RU486 inhibitor treatment decrease PTGR2 promoter activity and mRNA expression 21 3.6 GRE is important for PTGR2 promoter activation 21 3.7 Direct binding of GR and GRE on PTGR2 promoter 22 3.8 Dexamethasone pulse therapy significantly increase PTGR2 mRNA level 23 4. Conclusion 24 5. Discussion 24 5.1 Genome-wide search for GRE 24 5.2 Insulin signaling in regulation of PTGR2 26 5.3 Promoter deletion assay indicates presence of a transcriptional repressor 27 5.4 PTGR2 and glucocorticoids-induced insulin resistance 28 Figure 29 Tables 39 Supplementary Figure 42 References 42 | |
| dc.language.iso | en | |
| dc.subject | GR | zh_TW |
| dc.subject | 脂肪前驅細胞 | zh_TW |
| dc.subject | PTGR2 | zh_TW |
| dc.subject | Dexamethasone | zh_TW |
| dc.subject | 轉錄調節 | zh_TW |
| dc.subject | PTGR2 | en |
| dc.subject | glucocorticoids | en |
| dc.subject | GR | en |
| dc.subject | transcriptional regulation | en |
| dc.subject | 3T3-L1 cells. | en |
| dc.title | 葡萄糖激素受體對前列腺素還原酶-2基因表現調節之研究 | zh_TW |
| dc.title | The role of Glucocorticoid receptor(GR) in PTGR2 regulation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 許稟寧(Ping-Ning Hsu),徐立中(Li-Chung Hsu),林婉婉(Wan-Wan Lin) | |
| dc.subject.keyword | PTGR2,Dexamethasone,GR,轉錄調節,脂肪前驅細胞, | zh_TW |
| dc.subject.keyword | PTGR2,glucocorticoids,GR,transcriptional regulation,3T3-L1 cells., | en |
| dc.relation.page | 47 | |
| dc.identifier.doi | 10.6342/NTU201701785 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-07-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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