請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/87364完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蘇剛毅 | zh_TW |
| dc.contributor.advisor | Kang-Yi Su | en |
| dc.contributor.author | 廖耿楙 | zh_TW |
| dc.contributor.author | Keng-Mao Liao | en |
| dc.date.accessioned | 2023-05-18T17:18:10Z | - |
| dc.date.available | 2025-07-31 | - |
| dc.date.copyright | 2023-06-14 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-02-14 | - |
| dc.identifier.citation | Part I:
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/87364 | - |
| dc.description.abstract | 在第一部分，老化相關的健康問題隨人口逐漸老化而日漸重要，因此開發抗老化藥物是目前重要的課題，過去粒線體已經被證明參與細胞老化的過程，但針對此特徵的抗老藥物卻鮮少被探索，因此在本研究，我們證明二苯碘鎓 (Diphenyleneiodonium, DPI)可以顯著促進粒線體分裂與抑制其呼吸，在不同的細胞老化模型的評估下，二苯碘鎓減少了各項老化的標誌，同時抑制了老化造成的高呼吸率，此外，利用老化老鼠來測試二苯碘鎓抗老化的能力，發現其不僅可以減少老化標誌，也可以減緩老化相關的肝臟纖維化及免疫細胞浸潤，最後，二苯碘鎓也可以改善老化所造成的生理功能退化。總而言之，二苯碘鎓是一個具有抗老化能力藥物，未來可以單獨或合併其他抗老藥物來改善老化相關的疾病或狀態。第二部分， 微小核糖核酸 (MicroRNA) 可以透過影響訊息核糖核酸來調控基因表達，進而參與在許多細胞及生理功能，其中microRNA-137 (miR-137)不僅在不同物種中具有保守性且在神經系統中高度表達，並且調控神經發育與功能，另外也參與在各種癌症的病程，然而miR-137是否參與其他生理功能及癌症生成的角色尚未闡明，因此本研究主要透過在小鼠上剔除Mir137來探索其在活體之功能。有趣的是，Mir137 剔除鼠出現許多表現型包括成長遲緩、出生後死亡、骨質疏鬆、脂肪萎縮、低血糖、低體溫。進一步探索Mir137缺失導致成長遲緩的原因，我們發現Growth hormone (GH)/Insulin-like growth factor 1 (IGF1) 軸被破壞，血清的IGF1降低並伴隨GH的上升，透過體外及體內的實驗發現，Mir137缺失會導致非細胞自主性的GH阻抗，最後利用Cre/LoxP 系統確認了小鼠腦部Mir137的缺失會導致此現象。總結來說，腦部miR-137可以透過影響GH/IGF1途徑來調控身體成長。 | zh_TW |
| dc.description.abstract | In the part I: As the population ages, health issues with aging are becoming increasingly important, making the development of anti-aging drugs a current topic of interest. Previous research has shown that mitochondria play a role in the aging process, but the use of anti-aging drugs targeting this feature has been rare. In this study, we found that Diphenyleneiodonium (DPI) significantly increased mitochondrial fission and suppressed its respiration. When evaluated DPI effect on various models of cell senescence, DPI reduced various senescence markers and decreased the senescence-induced hyper oxygen consumption rate. Additionally, when tested on aging mice, DPI was found to not only reduce senescence markers, but also slow down aging-related liver fibrosis and infiltration of immune cells. It also improved the deterioration of physiological functions caused by aging. Overall, DPI is an effective anti-aging drug that can be used alone or in combination with other anti-aging drugs to improve aging-related diseases or conditions in the future. In the part II: MicroRNA can regulate gene expression by affecting messenger RNA and is involved in many cellular and physiological functions. Mir137 is high conservation in various species and highly expressed in neuron system. It plays a role in neurodevelopment and function, as well as various cancers. However, the role of miR-137 in physiological functions and cancer development is not yet fully clarification. In this study, we explored the function of miR-137 in mice by eliminating it. Interestingly, Mir137 knockout mice displayed several phenotypes including growth retardation, postnatal death, osteoporosis, lipoatrophy, hypoglycemia, and hypothermia. To further understand the cause of the growth retardation caused by the loss of Mir137, we found that Growth hormone (GH)/Insulin-like growth factor (IGF1) axis was disrupted and serum IGF1 decreased with an increase in GH. Through in vitro and in vivo experiments, we discovered that the loss of Mir137 led to non-cell-autonomous GH resistance. Finally, using the Cre/LoxP system, we confirmed that the loss of Mir137 in the mouse brain led to this phenomenon. In summary, brain miR-137 can regulate body growth by affecting the GH/IGF1 pathway. | en |
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| dc.description.tableofcontents | CONTENTS
致謝 I 摘要 II ABSTRACT IV CONTENTS VI LIST OF FIGURES XXII LIST OF TABLES XXX PART I: SENOMORPHIC EFFECT OF DIPHENYLENEIODONIUM THROUGH AMPK/MFF/DRP1 MEDIATED MITOCHONDRIAL FISSION. 1 二苯碘鎓透過AMPK/MFF/DRP1主導粒線體分裂以抗老化 1 摘要 2 Abstract 3 A. Introduction: 5 1. Aging 5 2. Cellular senescence 5 2.1 Cell-cycle arrest 6 2.1.1 The p53/p21 pathway 6 2.1.2 p16/pRB pathway 7 2.2 Senescence-associated secretory phenotype 7 2.3 Morphological changes 8 2.3.1 Cell size 8 2.3.2 Cellular granularity 8 2.4 Senescence-associated β-galactosidase 9 3. Stress-induced cellular senescence 9 3.1 Telomere dysfunction and DNA damage 9 3.2 Oncogene activation 10 3.3 Oxidative stress 10 4. Mitochondria and cellular senescence 11 4.1 Mitochondrial morphology dynamics 12 4.1.1 Mitochondrial fusion proteins 13 4.1.1.1 Mitofusin1/2 (MFN1/2) 13 4.1.1.2 Optic atrophy 1 (OPA1) 13 4.1.2 Mitochondrial fission proteins 14 4.1.2.1 DRP1 14 4.1.2.1 Phosphorylation 15 4.1.2.2 SUMOylation 16 4.1.2.3 Ubiquitination 16 4.1.2.4 Palmitoylation 17 4.1.2.5 S-nitrosylation 18 4.1.2.6 O-GlcNAcylation 19 4.1.2.7 DRP1 recruitment factors 19 4.2 Mitochondrial morphology dysregulation and aging 20 4.2.1 Saccharomyces cerevisiae 20 4.2.2 Caenorhabditis elegans 21 4.2.3 Drosophila melanogaster 22 4.2.4 Mus musculus and Homo sapiens 23 5. Elimination of senescent cells 24 5.1 Senolytic drugs 24 5.2 Senomorphic drug 24 5.3 Cell therapy 25 6. Targeting mitochondria to clear senescent cells 25 7. Cell and animal models for aging research 26 7.1 Cell models of senescence 26 7.1.1 Replicative senescence 26 7.1.2 Stress-induced senescence 27 7.1.3 Oncogene-induced senescence 27 7.2 Mouse models of aging 27 7.2.1 Aging mice model 27 7.2.2 Lung senescence and fibrosis model 28 7.2.3 Senescent-cell transplantation model 28 8. Diphenyleneiodonium chloride (DPI) 29 9. Specific aim: 29 B. Material and Method: 30 1. Cell culture and treatments 30 2. Animal experiments 31 3. Aged mice model 31 4. Bleomycin-induced lung fibrosis model 31 5. Immunofluorescence staining 32 6. Cell viability assay 33 7. Mitochondrial respiration detection by Seahorse analysis 33 8. Tetramethylrhodamine (TMRM) staining 34 9. SA-β galactosidase (SA-β-gal) staining 34 10. Western blots and antibodies 35 11. Reverse transcription (RT)-qPCR 37 12. Cell size analysis by flow cytometry 37 13. Reactive oxygen species (ROS) detection by flow cytometry 37 14. Masson’s trichrome staining 38 15. Immunohistochemistry staining and antibodies 38 16. Physical function test 39 17. Lung function test 39 18. Statistical analysis 40 C. Result: 41 1. Potential anti-senescence compound was identified by mitochondrial morphology regulation. 41 2. Low dosage DPI repressed mitochondrial respiration without cytotoxicity. 42 3. DPI attenuates senescence in both stress- and replication-induced cell models 44 4. DPI-induced mitochondrial fragmentation was mediated by AMPK/MFF/DRP1 axis. 46 5. DPI effect of anti-senescence is contributed by DRP1-mediated mitochondrial fission. 48 6. Senescence markers is reduced in aged mice by DPI treatment 49 7. DPI treatment improves age-related histopathological changes and restore physical functions in aged mice 50 8. DPI improves bleomycin-induced lung fibrosis 51 D. Discussion: 52 E. Figure: 57 Figure 1. Mitochondrial morphology changes of senescent MEF cells. 57 Figure 2. Cell viability test of cortisone, TBBz, DPI. 58 Figure 3. DPI dramatically down regulated mitochondrial oxygen consumption rate in NIH3T3 cells. 59 Figure 4. DPI dose-dependent decreased mitochondrial oxygen consumption rate and mitochondrial membrane potential in NIH3T3 cells. 60 Figure 5. Low concentration of DPI showed without cytotoxicity in short- and long-term treatment. 62 Figure 6. BrdU treatment induced cellular senescence dose-dependently. 63 Figure 7. Expression of cell cycle arrest genes and SASP factors were evaluated after BrdU treatment. 65 Figure 8. DPI reduced SA-β gal activity and increased proliferation marker Ki-67 in BrdU-induced NIH3T3 senescence model. 67 Figure 9. DPI reduced senescence markers in BrdU-induced NIH3T3 senescence model. 68 Figure 10. DPI treatment improved mitochondrial elongation and reduced the level of ROS in BrdU-induced senescent NIH3T3 cells. 69 Figure 11. DPI reversed mitochondrial respiration change in BrdU-induced NIH3T3 senescent cells. 71 Figure 12. Replicative cellular senescence was presented of MEFs after serial cell culture. 72 Figure 13. Expression of cell cycle arrest genes and SASP genes in senescent MEF cells. 73 Figure 14. DPI treatment reduced SA-β gal activity and increased proliferation marker Ki-67 in MEFs. 74 Figure 15. DPI reduced senescence markers in senescent MEFs. 75 Figure 16. DPI reversed mitochondrial respiration change in senescent MEFs. 77 Figure 17. Irradiation (IR) induced mitochondrial elongation. 78 Figure 18. DPI attenuate BrdU- and IR-induced cellular senescence in IMR90 cells. 79 Figure 19. DPI showed that did not specifically reduce senescent cells. 81 Figure 20. Translocation of DRP1 to mitochondria was increased by DPI treatment. 82 Figure 21. DPI treatment did not alter the expression of DRP1 recruitment proteins and DRP1 phosphorylation. 83 Figure 22. DPI promoted MFF phosphorylation via AMPK pathway. 85 Figure 23. Inhibition of Drp1 reversed DPI induced mitochondrial fragmentation. 86 Figure 24. Inhibition of DRP1 activity reversed DPI-induced mitochondrial respiration change. 87 Figure 25. DRP1 activity inhibition by Mdivi-1 reversed DPI anti-senescence effect in MEFs. 88 Figure 26. Mdivi-1 treatment reversed DPI effect on reduction of senescence markers. 89 Figure 27. Mdivi-1 reversed DPI-induced mitochondrial respiration change in senescent MEFs. 90 Figure 28. DPI enhanced mitochondria fragmentation in senescent MEFs through the action of DRP1 but failed to inhibit ROS production in the short term. 91 Figure 29. DPI treatment promoted DRP1 mitochondrial translocation in senescent MEFs and did not affect mitochondrial dynamic protein expression. 93 Figure 30. Mdivi-1 reversed DPI induced mitochondrial fragmentation and ROS change in senescent MEFs in long-term treatment. 94 Figure 31. DPI toxicity was tested in mice. 96 Figure 32. DPI reduced SA-β gal activity in kidney without liver toxicity in mice. 97 Figure 33. DPI reduced cell cycle arrest genes in liver and kidney of mice. 98 Figure 34. DPI reduced SASP genes in liver and kidney of mice with DPI treatment. 99 Figure 35. Mice treated with DPI that showed without body weight change and liver toxicity. 100 Figure 36. Treatment with DPI resulted in a reduction in the number of SA-β positive cells in the liver and kidney of aged mice. 102 Figure 37. Expression of cell cycle arrest genes Cdkn1a and Cdkn2a mRNA in the livers and kidneys of aged mice was assessed following DPI treatment. 104 Figure 38. The expression pattern of SASP factors in the liver and kidney of aged mice was examined after DPI treatment. 105 Figure 39. The DPI treatment leads to a reduction in immune cell infiltration and an improvement in liver fibrosis in aged mice. 106 Figure 40. DPI treatment enhances the physiological capabilities of aged mice. 108 Figure 41. DPI treatment improved lung fibrosis and reduced cell cycle arrest gene expression in bleomycin-induced mice. 109 Figure 42. DPI treatment improved SASP expression in lung tissue of bleomycin-induced mice. 111 Figure 43. DRP1 phosphorylation was not altered by ROS. 112 Figure 44. Summary. 113 F. Table: 114 Table 1. Primer list of QPCR 114 G. Reference 116 H. Appendix 140 PART II: INVESTIGATION OF MIR-137 ROLE IN PHYSIOLOGICAL FUNCTIONS: FOCUS ON GROWTH RETARDATION. 151 探究MIR-137在生理功能上所扮演的角色: 專注於成長遲緩 151 摘要 152 Abstract 154 A. Introduction: 156 1. The growth hormone and insulin-like growth factor 1 axis (GH/IGF1 axis) 156 1.1 Growth hormone: 156 1.1.1 Growth hormone signal transduction: 157 1.1.2 Whole-body Ghr KO mice: 158 1.1.3 Liver-specific KO mice: 158 1.1.4 Intestinal epithelial Ghr KO mice: 159 1.1.5 Adipocyte Ghr KO mice: 160 1.1.6 Brain Ghr KO mice: 161 1.1.7 Muscle Ghr KO mice: 162 1.1.8 Bone Ghr KO mice 163 1.2 Insulin-like growth factor 1 (IGF1): 163 1.2.1 IGF1 signal transduction: 164 1.2.2 Igf1 whole-body KO mice: 164 1.2.3 Liver Igf1 KO mice: 165 1.2.4 Igf1r KO mice: 166 1.3 Regulation of the GH/IGF1 Axis: 166 1.3.1 Regulation of GH expression and secretion: 166 1.3.2 Regulation of IGF1 expression and secretion: 167 1.3.3 Non-cell-autonomous regulation of the GH/IGF1 axis for body growth control 168 2. Body growth disorders: 169 2.1 Malnutrition 170 2.2 Growth hormone deficiency (GHD) 170 2.3 Hypothyroidism 170 2.4 Chronic diseases 170 2.5 Genetic syndromes 171 3. MicroRNA (miRNA): 171 3.1. MicroRNA in body growth regulation: 172 3.2. MicroRNA-137: 174 4. Specific aim: 175 B. Materials and Methods: 176 1. Production of mice with tissue-specific Mir137 deletion: 176 2. Polymerase chain reaction (PCR): 176 3. Real-time quantitative PCR (QPCR): 176 4. Western blot: 177 5. Complete blood count (CBC): 178 6. Hematoxylin and eosin staining (H&E staining): 178 7. Trabecular bone (TB) and bone mineral density (BMD) detection by micro-tomography (micro-CT): 179 8. Body temperature measurement via infrared camera: 179 9. Blood glucose detection: 179 10. Enzyme-linked immunosorbent assay (ELISA): 180 11. Recombinant protein treatment: 180 12. Primary hepatocyte isolation and GH pathway analysis: 180 13. cDNA microarray and RNA sequencing: 181 14. Statistical analysis 182 C. Results: 183 1. Successful creation of Mir137 knockout mice 183 2. Expression profiling of miR-137 in brain areas and the effect on brain cell population 183 3. Mir137 KO mice showed severe postnatal growth retardation and early death 184 4. Abnormalities in bone and adipose tissues were found in Mir137 KO mice 185 5. Hepatic IGF1 production was disrupted in Mir137 KO mice 187 6. Hepatic IGF1 suppression was regulated via non-cell-autonomous pathway 189 7. miR-137 deficiency led to GH resistance 190 8. Growth retardation in Mir137 KO mice did not occur through the starvation pathway 191 9. Brain-specific deletion of miR-137 led to growth retardation 192 10. MiR-137 deficiency did not affect GDF15 expression in tissues 194 11. Analysis of liver and brain gene expression 194 D. Discussion: 196 E. Figure: 203 Figure 1. Targeting strategy for Mir137 knockout by homologous recombination. 203 Figure 2. Expression of Mir137 in organs was measured via Taqman real-time polymerase chain reaction (RT-PCR) analysis. 204 Figure 3. Expression profiling of Mir137 in several brain areas. 206 Figure 4. Highest expression of Mir137 in P14 brain. 207 Figure 5. miR-137 deficiency did not affect cell populations in the brain. 208 Figure 6. Mir137 KO mice showed severe growth retardation. 209 Figure 7. Major organs were smaller in miR-137-deficient mice. 210 Figure 8. There was no difference in body size between WT (+/+) and KO (−/−) mice at P1. 211 Figure 9. Mir137 knockout mice showed early postnatal death. 212 Figure 10. Complete blood count (CBC) for miR-137-deficient mice. 213 Figure 11. Histology analysis of miR-137-deficient mice. 215 Figure 12. Osteoporosis was found in Mir137 knockout mice. 216 Figure 13. Brown and white fatty tissues were smaller in extent in miR-137-deficient mice. 217 Figure 14. miR-137 deficiency led to adipose tissue atrophy. 219 Figure 15. Expression pattern of markers of browning adipocytes in white fatty tissue. 220 Figure 16. miR-137 deficiency caused hypoglycemia. 221 Figure 17. Mir137 knockout led to hypothermia. 222 Figure 18. Expression of hepatic Igf1 and Igf1-associated genes was disrupted in Mir137 knockout mice. 223 Figure 19. miR-137 deficiency did not affect Igf1 mRNA expression in other organs, but it induced Igf1r mRNA expression. 224 Figure 20. Positive correlation of serum IGF1 with body weight. 225 Figure 21. AKT and ERK phosphorylation downregulated in miR-137-deficient tissues. 226 Figure 22. Liver p-STAT5 expression was downregulated in Mir137 KO mice. 227 Figure 23. miR-137 deficiency impaired GH-downstream processes only in the liver. 228 Figure 24. miR-137 deficiency did not affect hepatocyte GH signaling under GH stimulation. 229 Figure 25. Analysis of GH expression in pituitary gland and serum. 230 Figure 26. Exogenous growth hormone (GH) injection induced rapid phosphorylation of STAT5. 231 Figure 27. miR-137 deficiency suppressed phosphorylation of STAT5 under exogenous GH stimulation. 232 Figure 28. Exogenous ghrelin facilitated endogenous GH secretion and hepatic STAT5 phosphorylation. 233 Figure 29. Phosphorylation of STAT5 was suppressed in miR-137-deficient mice under ghrelin treatment. 234 Figure 30. GH receptor (GHR) mRNA expression was significantly reduced in liver and brain of miR-137-deficient mice. 235 Figure 31. Liver starvation gene expression. 236 Figure 32. Expression of starvation markers was monitored in mouse liver and serum. 237 Figure 33. Autophagy as a starvation marker could be used to monitor the status of mice. 238 Figure 34. miR-137 deficiency did not lead to autophagy activation. 239 Figure 35. Tissue-specific knockout of Mir137 was obtained using the Cre-LoxP system. 240 Figure 36. Specific knockout of Mir137 in the brain led to growth retardation. 241 Figure 37. Expression of GH signaling pathway and GH-downstream genes was dramatically reduced in brain-specific KO mice. 242 Figure 38. STAT5 phosphorylation levels were lower under KO serum treatment. 243 Figure 39. miR-137 was highly expressed in the right atrium. 244 Figure 40. Deletion of Mir137 did not affect Gdf15 expression in the heart or other organs. 245 Figure 41. Gene-expression analysis of miR-137-deficient mice. 246 Figure 42. Quality control of liver microarray. 247 Figure 43. Pathway map and Go process analysis for liver genes through MetaCore. 248 Figure 44. Selected genes from brain next-generation sequencing data were validated via QPCR and ELISA. 249 Figure 45. Deletion of miR-137 in the brain resulted in impaired function of the GH/IGF1 axis and postnatal growth retardation via the endocrine pathway. 250 F. Table 251 Table 1. Primer for genotyping. 251 Table 2. Primers for QPCR 252 Table 3. The Statistic of genotype in offspring. 255 Table 4. Gene list: Partial of genes dose-dependent up-regulated in brain of Mir137 deficiency mice 256 G. Reference: 259 H. Appendix 274 LIST OF FIGURES Part I: Figure 1. Mitochondrial morphology changes of senescent MEF cells. 57 Figure 2. Cell viability test of cortisone, TBBz, DPI. 58 Figure 3. DPI dramatically down regulated mitochondrial oxygen consumption rate in NIH3T3 cells. 59 Figure 4. DPI dose-dependent decreased mitochondrial oxygen consumption rate and mitochondrial membrane potential in NIH3T3 cells. 60 Figure 5. Low concentration of DPI showed without cytotoxicity in short- and long-term treatment. 62 Figure 6. BrdU treatment induced cellular senescence dose-dependently. 63 Figure 7. Expression of cell cycle arrest genes and SASP factors were evaluated after BrdU treatment. 65 Figure 8. DPI reduced SA-β gal activity and increased proliferation marker Ki-67 in BrdU-induced NIH3T3 senescence model. 67 Figure 9. DPI reduced senescence markers in BrdU-induced NIH3T3 senescence model. 68 Figure 10. DPI treatment improved mitochondrial elongation and reduced the level of ROS in BrdU-induced senescent NIH3T3 cells. 69 Figure 11. DPI reversed mitochondrial respiration change in BrdU-induced NIH3T3 senescent cells. 71 Figure 12. Replicative cellular senescence was presented of MEFs after serial cell culture. 72 Figure 13. Expression of cell cycle arrest genes and SASP genes in senescent MEF cells. 73 Figure 14. DPI treatment reduced SA-β gal activity and increased proliferation marker Ki-67 in MEFs. 74 Figure 15. DPI reduced senescence markers in senescent MEFs. 75 Figure 16. DPI reversed mitochondrial respiration change in senescent MEFs. 77 Figure 17. Irradiation (IR) induced mitochondrial elongation. 78 Figure 18. DPI attenuate BrdU- and IR-induced cellular senescence in IMR90 cells. 79 Figure 19. DPI showed that did not specifically reduce senescent cells. 81 Figure 20. Translocation of DRP1 to mitochondria was increased by DPI treatment. 82 Figure 21. DPI treatment did not alter the expression of DRP1 recruitment proteins and DRP1 phosphorylation. 83 Figure 22. DPI promoted MFF phosphorylation via AMPK pathway. 85 Figure 23. Inhibition of Drp1 reversed DPI induced mitochondrial fragmentation. 86 Figure 24. Inhibition of DRP1 activity reversed DPI-induced mitochondrial respiration change. 87 Figure 25. DRP1 activity inhibition by Mdivi-1 reversed DPI anti-senescence effect in MEFs. 88 Figure 26. Mdivi-1 treatment reversed DPI effect on reduction of senescence markers. 89 Figure 27. Mdivi-1 reversed DPI-induced mitochondrial respiration change in senescent MEFs. 90 Figure 28. DPI enhanced mitochondria fragmentation in senescent MEFs through the action of DRP1 but failed to inhibit ROS production in the short term. 91 Figure 29. DPI treatment promoted DRP1 mitochondrial translocation in senescent MEFs and did not affect mitochondrial dynamic protein expression. 93 Figure 30. Mdivi-1 reversed DPI induced mitochondrial fragmentation and ROS change in senescent MEFs in long-term treatment. 94 Figure 31. DPI toxicity was tested in mice. 96 Figure 32. DPI reduced SA-β gal activity in kidney without liver toxicity in mice. 97 Figure 33. DPI reduced cell cycle arrest genes in liver and kidney of mice. 98 Figure 34. DPI reduced SASP genes in liver and kidney of mice with DPI treatment. 99 Figure 35. Mice treated with DPI that showed without body weight change and liver toxicity. 100 Figure 36. Treatment with DPI resulted in a reduction in the number of SA-β positive cells in the liver and kidney of aged mice. 102 Figure 37. Expression of cell cycle arrest genes Cdkn1a and Cdkn2a mRNA in the livers and kidneys of aged mice was assessed following DPI treatment. 104 Figure 38. The expression pattern of SASP factors in the liver and kidney of aged mice was examined after DPI treatment. 105 Figure 39. The DPI treatment leads to a reduction in immune cell infiltration and an improvement in liver fibrosis in aged mice. 106 Figure 40. DPI treatment enhances the physiological capabilities of aged mice. 108 Figure 41. DPI treatment improved lung fibrosis and reduced cell cycle arrest gene expression in bleomycin-induced mice. 109 Figure 42. DPI treatment improved SASP expression in lung tissue of bleomycin-induced mice. 111 Figure 43. DRP1 phosphorylation was not altered by ROS. 112 Figure 44. Summary. 113 Part II Figure 1. Targeting strategy for Mir137 knockout by homologous recombination. 203 Figure 2. Expression of Mir137 in organs was measured via Taqman real-time polymerase chain reaction (RT-PCR) analysis. 204 Figure 3. Expression profiling of Mir137 in several brain areas. 206 Figure 4. Highest expression of Mir137 in P14 brain. 207 Figure 5. miR-137 deficiency did not affect cell populations in the brain. 208 Figure 6. Mir137 KO mice showed severe growth retardation. 209 Figure 7. Major organs were smaller in miR-137-deficient mice. 210 Figure 8. There was no difference in body size between WT (+/+) and KO (−/−) mice at P1. 211 Figure 9. Mir137 knockout mice showed early postnatal death. 212 Figure 10. Complete blood count (CBC) for miR-137-deficient mice. 213 Figure 11. Histology analysis of miR-137-deficient mice. 215 Figure 12. Osteoporosis was found in Mir137 knockout mice. 216 Figure 13. Brown and white fatty tissues were smaller in extent in miR-137-deficient mice. 217 Figure 14. miR-137 deficiency led to adipose tissue atrophy. 219 Figure 15. Expression pattern of markers of browning adipocytes in white fatty tissue. 220 Figure 16. miR-137 deficiency caused hypoglycemia. 221 Figure 17. Mir137 knockout led to hypothermia. 222 Figure 18. Expression of hepatic Igf1 and Igf1-associated genes was disrupted in Mir137 knockout mice. 223 Figure 19. miR-137 deficiency did not affect Igf1 mRNA expression in other organs, but it induced Igf1r mRNA expression. 224 Figure 20. Positive correlation of serum IGF1 with body weight. 225 Figure 21. AKT and ERK phosphorylation downregulated in miR-137-deficient tissues. 226 Figure 22. Liver p-STAT5 expression was downregulated in Mir137 KO mice. 227 Figure 23. miR-137 deficiency impaired GH-downstream processes only in the liver. 228 Figure 24. miR-137 deficiency did not affect hepatocyte GH signaling under GH stimulation. 229 Figure 25. Analysis of GH expression in pituitary gland and serum. 230 Figure 26. Exogenous growth hormone (GH) injection induced rapid phosphorylation of STAT5. 231 Figure 27. miR-137 deficiency suppressed phosphorylation of STAT5 under exogenous GH stimulation. 232 Figure 28. Exogenous ghrelin facilitated endogenous GH secretion and hepatic STAT5 phosphorylation. 233 Figure 29. Phosphorylation of STAT5 was suppressed in miR-137-deficient mice under ghrelin treatment. 234 Figure 30. GH receptor (GHR) mRNA expression was significantly reduced in liver and brain of miR-137-deficient mice. 235 Figure 31. Liver starvation gene expression. 236 Figure 32. Expression of starvation markers was monitored in mouse liver and serum. 237 Figure 33. Autophagy as a starvation marker could be used to monitor the status of mice. 238 Figure 34. miR-137 deficiency did not lead to autophagy activation. 239 Figure 35. Tissue-specific knockout of Mir137 was obtained using the Cre-LoxP system. 240 Figure 36. Specific knockout of Mir137 in the brain led to growth retardation. 241 Figure 37. Expression of GH signaling pathway and GH-downstream genes was dramatically reduced in brain-specific KO mice. 242 Figure 38. STAT5 phosphorylation levels were lower under KO serum treatment. 243 Figure 39. miR-137 was highly expressed in the right atrium. 244 Figure 40. Deletion of Mir137 did not affect Gdf15 expression in the heart or other organs. 245 Figure 41. Gene-expression analysis of miR-137-deficient mice. 246 Figure 42. Quality control of liver microarray. 247 Figure 43. Pathway map and Go process analysis for liver genes through MetaCore. 248 Figure 44. Selected genes from brain next-generation sequencing data were validated via QPCR and ELISA. 249 Figure 45. Deletion of miR-137 in the brain resulted in impaired function of the GH/IGF1 axis and postnatal growth retardation via the endocrine pathway. 250 LIST OF TABLES PartI: Table 1. Primer list of QPCR 114 Part II Table 1. Primer for genotyping. 251 Table 2. Primers for QPCR 252 Table 3. The Statistic of genotype in offspring. 255 Table 4. Gene list: Partial of genes dose-dependent up-regulated in brain of Mir137 deficiency mice 256 | - |
| dc.language.iso | en | - |
| dc.subject | 微小核糖核酸-137 | zh_TW |
| dc.subject | 成長賀爾蒙阻抗 | zh_TW |
| dc.subject | 成長遲緩 | zh_TW |
| dc.subject | 老化 | zh_TW |
| dc.subject | 二苯碘鎓 | zh_TW |
| dc.subject | 粒線體 | zh_TW |
| dc.subject | GH resistance | en |
| dc.subject | MiR-137 | en |
| dc.subject | Growth retardation | en |
| dc.subject | Diphenyleneiodonium | en |
| dc.subject | Aging | en |
| dc.subject | Mitochondria | en |
| dc.title | Part I: 二苯碘鎓透過AMPK/MFF/DRP1主導粒線體分裂以抗老化; Part II: 探究miR-137在生理功能上所扮演的角色: 專注於成長遲緩 | zh_TW |
| dc.title | Part I: Senomorphic Effect of Diphenyleneiodonium through AMPK/MFF/DRP1 Mediated Mitochondrial Fission; Part II: Investigation of miR-137 Role in Physiological Functions: Focus on Growth Retardation | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 楊泮池;周玉山;郭靜穎;張以承 | zh_TW |
| dc.contributor.oralexamcommittee | Pan-Chyr Yang;Yuh-Shan Jou;Ching-Ying Kuo;Yi-Cheng Chang | en |
| dc.subject.keyword | 老化,二苯碘鎓,粒線體,微小核糖核酸-137,成長遲緩,成長賀爾蒙阻抗, | zh_TW |
| dc.subject.keyword | Aging,Diphenyleneiodonium,Mitochondria,MiR-137,Growth retardation,GH resistance, | en |
| dc.relation.page | 284 | - |
| dc.identifier.doi | 10.6342/NTU202300422 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2023-02-15 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 基因體與系統生物學學位學程 | - |
| dc.date.embargo-lift | 2025-07-31 | - |
| 顯示於系所單位： | 基因體與系統生物學學位學程 | |
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