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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蔡欣祐 | zh_TW |
| dc.contributor.advisor | Hsin-Yue Tsai | en |
| dc.contributor.author | 蔡伊婷 | zh_TW |
| dc.contributor.author | Yi-Ting Tsai | en |
| dc.date.accessioned | 2023-09-13T16:11:53Z | - |
| dc.date.available | 2023-11-10 | - |
| dc.date.copyright | 2023-09-13 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-07-04 | - |
| dc.identifier.citation | 1. Martineau, C.N., N.V. Kirienko, and N. Pujol, Innate immunity in C. elegans. Curr Top Dev Biol, 2021. 144: p. 309-351.
2. Irazoqui, J.E., J.M. Urbach, and F.M. Ausubel, Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates. Nat Rev Immunol, 2010. 10(1): p. 47-58. 3. Anderson, S.M. and R. Pukkila-Worley, Immunometabolism in Caenorhabditis elegans. PLoS Pathog, 2020. 16(10): p. e1008897. 4. Nandakumar, M. and M.W. Tan, Gamma-linolenic and stearidonic acids are required for basal immunity in Caenorhabditis elegans through their effects on p38 MAP kinase activity. PLoS Genet, 2008. 4(11): p. e1000273. 5. Dasgupta, M., et al., NHR-49 Transcription Factor Regulates Immunometabolic Response and Survival of Caenorhabditis elegans during Enterococcus faecalis Infection. Infect Immun, 2020. 88(8). 6. Wang, B., et al., Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct Target Ther, 2021. 6(1): p. 94. 7. Soares, E.M., et al., Leukotriene B4 enhances innate immune defense against the puerperal sepsis agent Streptococcus pyogenes. J Immunol, 2013. 190(4): p. 1614-22. 8. Watts, J.L. and M. Ristow, Lipid and Carbohydrate Metabolism in Caenorhabditis elegans. Genetics, 2017. 207(2): p. 413-446. 9. Anderson, S.M., et al., The fatty acid oleate is required for innate immune activation and pathogen defense in Caenorhabditis elegans. PLoS Pathog, 2019. 15(6): p. e1007893. 10. Zhang, S., et al., The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis, 2022. 13(2): p. 132. 11. Matsushita, K., et al., Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature, 2009. 458(7242): p. 1185-90. 12. Habacher, C. and R. Ciosk, ZC3H12A/MCPIP1/Regnase-1-related endonucleases: An evolutionary perspective on molecular mechanisms and biological functions. Bioessays, 2017. 39(9). 13. Fischer, M., T. Weinberger, and C. Schulz, The immunomodulatory role of Regnase family RNA-binding proteins. RNA Biol, 2020. 17(12): p. 1721-1726. 14. Sobanska, D., et al., The silencing of ets-4 mRNA relies on the functional cooperation between REGE-1/Regnase-1 and RLE-1/Roquin-1. Nucleic Acids Res, 2022. 50(14): p. 8226-8239. 15. Habacher, C., et al., Ribonuclease-Mediated Control of Body Fat. Dev Cell, 2016. 39(3): p. 359-369. 16. Thyagarajan, B., et al., ETS-4 is a transcriptional regulator of life span in Caenorhabditis elegans. PLoS Genet, 2010. 6(9): p. e1001125. 17. Sharrocks, A.D., The ETS-domain transcription factor family. Nat Rev Mol Cell Biol, 2001. 2(11): p. 827-37. 18. Li, C., N. Hisamoto, and K. Matsumoto, Axon Regeneration Is Regulated by Ets-C/EBP Transcription Complexes Generated by Activation of the cAMP/Ca2+ Signaling Pathways. PLoS Genet, 2015. 11(10): p. e1005603. 19. Pekec, T., et al., Ferritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons. Nat Commun, 2022. 13(1): p. 4883. 20. Kenyon, C., et al., A C. elegans mutant that lives twice as long as wild type. Nature, 1993. 366(6454): p. 461-4. 21. Murphy, C.T. and P.J. Hu, Insulin/insulin-like growth factor signaling in C. elegans. WormBook, 2013: p. 1-43. 22. Murphy, C.T., et al., Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature, 2003. 424(6946): p. 277-83. 23. Furuyama, T., et al., Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem J, 2000. 349(Pt 2): p. 629-34. 24. Tepper, R.G., et al., PQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity. Cell, 2013. 154(3): p. 676-690. 25. Garsin, D.A., et al., Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens. Science, 2003. 300(5627): p. 1921. 26. Blackwell, T.K., et al., TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging. Genetics, 2019. 213(2): p. 329-360. 27. Nagahama, Y., et al., Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism. Proc Natl Acad Sci U S A, 2018. 115(43): p. 11036-11041. 28. Brenner, S., The genetics of Caenorhabditis elegans. Genetics, 1974. 77(1): p. 71-94. 29. Ghanta, K.S. and C.C. Mello, Melting dsDNA Donor Molecules Greatly Improves Precision Genome Editing in Caenorhabditis elegans. Genetics, 2020. 216(3): p. 643-650. 30. Tan, M.W., S. Mahajan-Miklos, and F.M. Ausubel, Killing of Caenorhabditis elegans by Pseudomonas aeruginosa used to model mammalian bacterial pathogenesis. Proc Natl Acad Sci U S A, 1999. 96(2): p. 715-20. 31. Yang, J.S., et al., OASIS: online application for the survival analysis of lifespan assays performed in aging research. PLoS One, 2011. 6(8): p. e23525. 32. Afgan, E., et al., The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update. Nucleic Acids Res, 2018. 46(W1): p. W537-W544. 33. Kim, D., B. Langmead, and S.L. Salzberg, HISAT: a fast spliced aligner with low memory requirements. Nat Methods, 2015. 12(4): p. 357-60. 34. Liao, Y., G.K. Smyth, and W. Shi, featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics, 2014. 30(7): p. 923-30. 35. Love, M.I., W. Huber, and S. Anders, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol, 2014. 15(12): p. 550. 36. Babicki, S., et al., Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res, 2016. 44(W1): p. W147-53. 37. O'Rourke, E.J., et al., C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. Cell Metab, 2009. 10(5): p. 430-5. 38. Hosack, D.A., et al., Identifying biological themes within lists of genes with EASE. Genome Biol, 2003. 4(10): p. R70. 39. Fuhrman, L.E., et al., Nucleolar proteins suppress Caenorhabditis elegans innate immunity by inhibiting p53/CEP-1. PLoS Genet, 2009. 5(9): p. e1000657. 40. Younce, C.W. and P.E. Kolattukudy, MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP. Biochem J, 2010. 426(1): p. 43-53. 41. Wang, K., et al., Osteoclast precursor differentiation by MCPIP via oxidative stress, endoplasmic reticulum stress, and autophagy. J Mol Cell Biol, 2011. 3(6): p. 360-8. 42. Roy, A. and P.E. Kolattukudy, Monocyte chemotactic protein-induced protein (MCPIP) promotes inflammatory angiogenesis via sequential induction of oxidative stress, endoplasmic reticulum stress and autophagy. Cell Signal, 2012. 24(11): p. 2123-31. 43. Richardson, C.E., T. Kooistra, and D.H. Kim, An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature, 2010. 463(7284): p. 1092-5. 44. Meisel, J.D., et al., Chemosensation of bacterial secondary metabolites modulates neuroendocrine signaling and behavior of C. elegans. Cell, 2014. 159(2): p. 267-80. 45. Angeles-Albores, D., et al., Tissue enrichment analysis for C. elegans genomics. BMC Bioinformatics, 2016. 17(1): p. 366. 46. Angeles-Albores, D., et al., Two new functions in the WormBase Enrichment Suite. MicroPubl Biol, 2018. 2018. 47. Yang, W., K. Dierking, and H. Schulenburg, WormExp: a web-based application for a Caenorhabditis elegans-specific gene expression enrichment analysis. Bioinformatics, 2016. 32(6): p. 943-5. 48. Kimura, K.D., et al., daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science, 1997. 277(5328): p. 942-6. 49. Chen, Z., et al., Two insulin-like peptides antagonistically regulate aversive olfactory learning in C. elegans. Neuron, 2013. 77(3): p. 572-85. 50. Davis, C.A., et al., The Encyclopedia of DNA elements (ENCODE): data portal update. Nucleic Acids Res, 2018. 46(D1): p. D794-D801. 51. Lamming, D.W. and D.M. Sabatini, A Central role for mTOR in lipid homeostasis. Cell Metab, 2013. 18(4): p. 465-9. 52. Simcox, J. and D.W. Lamming, The central moTOR of metabolism. Dev Cell, 2022. 57(6): p. 691-706. 53. Bouagnon, A.D., et al., Intestinal peroxisomal fatty acid beta-oxidation regulates neural serotonin signaling through a feedback mechanism. PLoS Biol, 2019. 17(12): p. e3000242. 54. Labrousse, A., et al., Caenorhabditis elegans is a model host for Salmonella typhimurium. Curr Biol, 2000. 10(23): p. 1543-5. 55. He, A., et al., Acetyl-CoA Derived from Hepatic Peroxisomal beta-Oxidation Inhibits Autophagy and Promotes Steatosis via mTORC1 Activation. Mol Cell, 2020. 79(1): p. 30-42 e4. 56. Son, S.M., et al., Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A. Cell Metab, 2019. 29(1): p. 192-201 e7. 57. Zhang, S.O., et al., Genetic and dietary regulation of lipid droplet expansion in Caenorhabditis elegans. Proc Natl Acad Sci U S A, 2010. 107(10): p. 4640-5. 58. Li, S., et al., A Genetic Screen for Mutants with Supersized Lipid Droplets in Caenorhabditis elegans. G3 (Bethesda), 2016. 6(8): p. 2407-19. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89640 | - |
| dc.description.abstract | 秀麗隱桿線蟲（Caenorhabditis elegans）以其短暫的生命週期和可操控的遺傳特性成為理想的模式生物。由於在秀麗隱桿線蟲中發現的基因和生理機制普遍存在於人類和其他物種中，透過瞭解同源蛋白質對於線蟲生理的影響，我們能夠更深入地了解該蛋白如何調控生物的生理機制，進而將這些瞭解應用於人類或其他物種。在本研究中，我們發現線蟲中的核糖核酸酶REGE-1（與哺乳動物的核糖核酸酶REGNASE-1同源）會影響線蟲在綠膿桿菌（PA14）感染下的存活率。。透過mRNA-Seq分析，我們在rege-1突變蟲中觀察到了兩個關鍵代謝途徑的基因群變化，即胰島素/類胰島素生長因子1（IGF-1）信號（IIS）途徑和TOR激酶信號途徑。抑制這兩條途徑中的任何一條都可以挽救rege-1突變蟲的低存活率。在胰島素/類胰島素生長因子信號（IIS）途徑中，線蟲daf-2基因可轉譯出人類胰島素樣生長因子1受體（IGF1R）的同源蛋白。研究發現，daf-2突變蟲體在正常條件下的壽命比野生型蟲體長。在daf-2突變蟲體中，基因變化可被分為兩類。第一類基因在daf-2基因突變下而表現量增加，而第二類基因在daf-2基因突變下而表現量減少，並且受到DAF-16/FoxO的調控。當我們在rege-1突變蟲中抑制屬於第二類基因之一的過氧化物酸β-氧化酶acox-1.5的表現時，我們觀察到蟲體脂肪含量顯著增加，並改善了rege-1突變蟲在感染過程中的存活率，並從過往的CHIP實驗中發現它受ETS-4調控。總結起來，我們的研究發現rege-1通過調節代謝途徑來影響宿主防禦的機制。 | zh_TW |
| dc.description.abstract | Due to its rapid life cycle and genetic manipulability, Caenorhabditis elegans (C. elegans) is widely used as a model organism for studying conserved pathways in higher organisms. By regulating post-transcriptional events, living organisms can rapidly respond to environmental stimuli. In this study, we showed that REGE-1 ribonuclease, an ortholog of mammalian Regnase-1, is required for lifespan extension under Pseudomonas aeruginosa (PA14). We found that the excess ets-4 mRNA expression, whose mRNA is post-transcriptional regulated by REGE-1 in C. elegans, was associated with higher susceptibility to PA14 infection in worms. Additionally, we discovered global gene changes in two key metabolic pathways, insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway and TOR (target of rapamycin) kinase signaling pathways, through mRNA-Seq analysis in rege-1 mutant worm. Genetic inhibition of either pathway was sufficient to rescue the poor survival of rege-1 mutant worms. The daf-2 gene encodes an ortholog of the human insulin-like growth factor 1 receptor (IGF1R). Two gene clusters have been identified in the insulin/insulin-like growth factor signaling (IIS) pathway. Class I genes are upregulated in daf-2 mutants, while Class II genes are downregulated in daf-2 mutants, and this regulation is dependent on DAF-16/FoxO. In our study, we observed higher expression of class II in rege-1 mutant worms, which may be targeted by ETS-4 and correlated with a higher susceptibility to PA14 infection. Furthermore, we discovered peroxisome acyl-CoA oxidase ACOX-1.5, which belongs to class II and is predicted to be regulated by ETS-4. When we genetically inhibited acox-1.5, we observed a significant rescue in fat content and improved survival of rege-1 mutant worms during infection. In conclusion, our study has revealed how rege-1 affects host defense by regulating metabolic pathways. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-13T16:11:53Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-09-13T16:11:53Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract ii Chapter 1 Introduction 1 1.1 Host defense involves lipid metabolism in C. elegans 1 1.2 Regulation of lipid metabolism during host defense in C. elegans 2 1.3 The post-transcriptional regulation of lipid metabolism by REGE-1 (REGnasE-1) ribonuclease in C. elegans 3 1.4 The regulation of ETS-4 under stress condition 5 1.5 Pathway involved in lipid metabolism and host defense 6 Chapter 2 Material and Method 10 2.1 Genetics 10 2.2 Generation of rege-1(imm070) allele 10 2.3 P. aeruginosa (PA14) killing assays 11 2.4 mRNA-Seq and analysis 12 2.5 RT-qPCR 13 2.6 PA14 clearance assay and avoidance assay 13 2.7 Oil red O staining and image quantification 14 2.8 Fluorescent imaging of Pins-7::GFP transcriptional reporter 15 2.9 Localization and quantification of transgene ets-4:gfp 15 2.10 Representation factor calculation 16 Chapter 3 Results 18 3.1 REGE-1 ribonuclease activity is required for lifespan extension and fat metabolism 18 3.2 REGE-1 ribonuclease activity extends C. elegans survival upon P. aeruginosa exposure. 19 3.3 REGE-1 and ETS-4 are indirectly involved in the response to ER stress. 20 3.4 REGE-1 and ETS-4 forms a regulation loop 22 3.5 Pathogen clearance and avoidance behavior defect are not the cause to hypersensitive rege-1(imm070) on PA14 23 3.6 REGE-1 negatively regulated gene were correlated with insulin/IGF-1 signaling pathway and Tor pathway 23 3.7 Insulin/IGF-1 signaling pathway contribute to hypersensitive rege-1(imm070) on PA14. 28 3.8 Suppressing TORC1 signaling rescues survival of PA14-fed rege-1(imm070) 30 3.9 ETS-4 highly expressed in nucleus when depletion of daf-16 and PQM-1 cannot rescue the shorter lifespan rege-1(imm070) 31 3.10 ETS-4 upregulated genes impair host defense 34 3.11 The effects of IIS pathway, mTOR pathway and peroxisome acid β-oxidation in lipid droplets formation in rege-1(imm070) 37 Chapter 4 Discussion 40 4.1 Malfunctional of grinder is not the reason to cause rege-1(imm070) hypersensitive to PA14 40 4.2 Role of ETS-4 in respond to environmental stress 41 4.3 The role of DAF-16, PQM-1 and ETS-4 in modulating longevity genes 42 4.4 Does lipid content affect immunity in rege-1(imm070) 43 4.5 The Role of ACOX-1.5 in TORC1 Signaling 43 4.6 The impact of peroxisomal fatty acid beta oxidation on rege-1 mutant phenotypes 44 Chapter 5 Figures 46 Figure 1 REGE-1 ribonuclease activity is required for lifespan extension and fat metabolism 47 Figure 2 REGE-1 is important for C. elegans survival under PA14 through modulating ets-4 49 Figure 3 The insensitivity to ER stress in rege-1 mutant strains is not mediated through the REGE-1/ETS-4 axis. 51 Figure 4 The rege-1 (imm070) strain exhibits normal abilities in terms of pathogen clearance and avoidance. 53 Figure 5 Statistic analyses of the DEGs dataset 55 Figure 6 Statistic analyses of the DEGs dataset after exclude ets-4(ok165) 57 Figure 7 rege-1 negatively regulated gene are enriched in class II genes and bound by ETS-4 and PQM-1 59 Figure 8 suppressing IIS and TOR pathway is sufficient to rescue the PA14 sensitivity of rege1(imm070) 61 Figure 9 ETS-4 highly expressed in nucleus when depletion of daf-16 and PQM-1 cannot rescue the shorter lifespan rege-1(imm070) 63 Figure 10 The predicted ETS-4 targeted genes in REGE-1 mediated PA14 survival 65 Figure 11 Comparable survival curve between wild-type and rege-1(imm070) after knocking down putative ETS-4 targeted genes. 67 Figure 12 The fat content in suppressing IIS pathway and TORC1 pathway 69 Figure 13 Model 70 Table 1 Overlapping rege-1 negatively regulated genes in OP50 and PA14 with existing datasets. 71 Table 2. The Pearson r correlation of the rege-1(imm070) differential expressed genes with daf-2(e1370);rsks-1(ok1255) in OP50 and PA14 72 Table S1: Summary of lifespan analysis 73 Table S2 Mean lifespan of individual experiment, Average mean lifespan, Mean lifespan relative to wild-type, Rescue percentage (%) 78 Table S3 primer list used in this study 82 Chapter 6 Appendix 84 Appendix 1 rege-1 negatively regulated gene are enriched in class II genes and bound by ETS-4 and PQM-1 85 Appendix 2 Repeats of survival curve 93 Chapter 7 Reference 94 | - |
| dc.language.iso | en | - |
| dc.title | 探討REGE-1如何透過代謝途徑以促進線蟲存活之研究 | zh_TW |
| dc.title | REGE-1 promotes C. elegans survival by modulating metabolic pathway | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 許翱麟;潘俊良;詹仕鵬;吳益群;黃舒宜 | zh_TW |
| dc.contributor.oralexamcommittee | Ao-Lin Hsu;Chun-Liang Pan;Shih-Peng Chan;Yi-Chun Wu;Shu-Yi Huang | en |
| dc.subject.keyword | 核糖核酸酶REGE-1,轉錄因子ETS-4,胰島素/類胰島素生長因子1（IGF-1）信號（IIS）途徑,TOR激酶信號途徑,過氧化物酸β-氧化酶ACOX-1.5, | zh_TW |
| dc.subject.keyword | REGE-1,ETS-4,insulin/insulin-like growth factor signaling (IIS),The target of rapamycin (TOR) kinase signaling pathways,peroxisome acyl-CoA oxidase ACOX-1.5, | en |
| dc.relation.page | 101 | - |
| dc.identifier.doi | 10.6342/NTU202301316 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2023-07-05 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 分子醫學研究所 | - |
| dc.date.embargo-lift | 2028-07-03 | - |
| 顯示於系所單位： | 分子醫學研究所 | |
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