請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57482完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 詹智強(Chih-Chiang Chan) | |
| dc.contributor.author | Wei-Hung Jung | en |
| dc.contributor.author | 榮偉宏 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:48:00Z | - |
| dc.date.available | 2019-10-09 | |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-25 | |
| dc.identifier.citation | Adachi-Yamada, T., T. Gotoh, I. Sugimura, M. Tateno, Y. Nishida, T. Onuki and H. Date
(1999). 'De novo synthesis of sphingolipids is required for cell survival by down-regulating c-Jun N-terminal kinase in Drosophila imaginal discs.' Mol Cell Biol 19(10): 7276-7286. Basu, J. and Z. Li (1998). 'The Des-1 protein, required for central spindle assembly and cytokinesis, is associated with mitochondria along the meiotic spindle apparatus and with the contractile ring during male meiosis in Drosophila melanogaster.' Mol Gen Genet 259(6): 664-673. Bauer, R., A. Voelzmann, B. Breiden, U. Schepers, H. Farwanah, I. Hahn, F. Eckardt, K. Sandhoff and M. Hoch (2009). 'Schlank, a member of the ceramide synthase family controls growth and body fat in Drosophila.' EMBO J 28(23): 3706-3716. Bucci, C., P. Thomsen, P. Nicoziani, J. McCarthy and B. van Deurs (2000). 'Rab7: a key to lysosome biogenesis.' Mol Biol Cell 11(2): 467-480. Chan, C. C., S. Scoggin, D. Wang, S. Cherry, T. Dembo, B. Greenberg, E. J. Jin, C. Kuey, A. Lopez, S. Q. Mehta, T. J. Perkins, M. Brankatschk, A. Rothenfluh, M. Buszczak and P. R. Hiesinger (2011). 'Systematic discovery of Rab GTPases with synaptic functions in Drosophila.' Curr Biol 21(20): 1704-1715. Cherry, S., E. J. Jin, M. N. Ozel, Z. Lu, E. Agi, D. Wang, W. H. Jung, D. Epstein, I. A. Meinertzhagen, C. C. Chan and P. R. Hiesinger (2013). 'Charcot-Marie-Tooth 2B mutations in rab7 cause dosage-dependent neurodegeneration due to partial loss of function.' Elife 2: e01064. Chotard, C., W. Leung and I. Salecker (2005). 'glial cells missing and gcm2 cell autonomously regulate both glial and neuronal development in the visual system of Drosophila.' Neuron 48(2): 237-251. Chua, C. E., B. Q. Gan and B. L. Tang (2011). 'Involvement of members of the Rab family and related small GTPases in autophagosome formation and maturation.' Cell Mol Life Sci 68(20): 3349-3358. Cowart, L. A., Z. Szulc, A. Bielawska and Y. A. Hannun (2002). 'Structural determinants of sphingolipid recognition by commercially available anti-ceramide antibodies.' J Lipid Res 43(12): 2042-2048. Debattisti, V., D. Pendin, E. Ziviani, A. Daga and L. Scorrano (2014). 'Reduction of endoplasmic reticulum stress attenuates the defects caused by Drosophila mitofusin depletion.' J Cell Biol 204(3): 303-312. Endo, K., T. Akiyama, S. Kobayashi and M. Okada (1996). 'Degenerative spermatocyte, a novel gene encoding a transmembrane protein required for the initiation of meiosis in Drosophila spermatogenesis.' Mol Gen Genet 253(1-2): 157-165. Gagliostro, V., J. Casas, A. Caretti, J. L. Abad, L. Tagliavacca, R. Ghidoni, G. Fabrias and P. Signorelli (2012). 'Dihydroceramide delays cell cycle G1/S transition via activation of ER stress and induction of autophagy.' Int J Biochem Cell Biol 44(12): 2135-2143. Ghosh, A., T. Kling, N. Snaidero, J. L. Sampaio, A. Shevchenko, H. Gras, B. Geurten, M. C. Gopfert, J. B. Schulz, A. Voigt and M. Simons (2013). 'A global in vivo Drosophila RNAi screen identifies a key role of ceramide phosphoethanolamine for glial ensheathment of axons.' PLoS Genet 9(12): e1003980. Goldstein, L. S. B. and S. Gunawardena (2000). Table S2. Identified cytoskeletal protein coding genes in Drosophila. 150. Holthuis, J. C., T. Pomorski, R. J. Raggers, H. Sprong and G. Van Meer (2001). 'The organizing potential of sphingolipids in intracellular membrane transport.' Physiol Rev 81(4): 1689-1723. Jin, E. J., C. C. Chan, E. Agi, S. Cherry, E. Hanacik, M. Buszczak and P. R. Hiesinger (2012). 'Similarities of Drosophila rab GTPases based on expression profiling: completion and analysis of the rab-Gal4 kit.' PLoS One 7(7): e40912. Kawano, M., K. Kumagai, M. Nishijima and K. Hanada (2006). 'Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMPassociated protein-interacting FFAT motif of CERT.' J Biol Chem 281(40): 30279-30288. Kroemer, G. and B. Levine (2008). 'Autophagic cell death: the story of a misnomer.' Nat Rev Mol Cell Biol 9(12): 1004-1010. Kuhnlein, R. P. (2011). 'The contribution of the Drosophila model to lipid droplet research.' Prog Lipid Res 50(4): 348-356. Kumagai, K., S. Yasuda, K. Okemoto, M. Nishijima, S. Kobayashi and K. Hanada (2005). 'CERT mediates intermembrane transfer of various molecular species of ceramides.' J Biol Chem 280(8): 6488-6495. Mavromatakis, Y. E. and A. Tomlinson (2012). 'The role of the small GTPase Rap in Drosophila R7 photoreceptor specification.' Proceedings of the National Academy of Sciences of the United States of America 109(10): 3844-3849. Menasche, G., E. Pastural, J. Feldmann, S. Certain, F. Ersoy, S. Dupuis, N. Wulffraat, D. Bianchi, A. Fischer, F. Le Deist and G. de Saint Basile (2000). 'Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome.' Nat Genet 25(2): 173-176. Mitra, S., K. W. Cheng and G. B. Mills (2011). 'Rab GTPases implicated in inherited and acquired disorders.' Semin Cell Dev Biol 22(1): 57-68. Newsome, T. P., B. Asling and B. J. Dickson (2000). 'Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics.' Development 127(4): 851-860. Park, Y., W. Kim, A. Y. Kim, H. J. Choi, J. K. Choi, N. Park, E. K. Koh, J. Seo and Y. H. Koh (2011). 'Normal prion protein in Drosophila enhances the toxicity of pathogenic polyglutamine proteins and alters susceptibility to oxidative and autophagy signaling modulators.' Biochem Biophys Res Commun 404(2): 638-645. Pepperl, J., G. Reim, U. Luthi, A. Kaech, G. Hausmann and K. Basler (2013). 'Sphingolipid depletion impairs endocytic traffic and inhibits Wingless signaling.' Mech Dev 130(9-10): 493-505. Pettus, B. J., C. E. Chalfant and Y. A. Hannun (2002). 'Ceramide in apoptosis: an overview and current perspectives.' Biochim Biophys Acta 1585(2-3): 114-125. Poteryaev, D., S. Datta, K. Ackema, M. Zerial and A. Spang (2010). 'Identification of the switch in early-to-late endosome transition.' Cell 141(3): 497-508. Ross, J., H. Jiang, M. R. Kanost and Y. Wang (2003). 'Serine proteases and their homologs in the Drosophila melanogaster genome: an initial analysis of sequence conservation and phylogenetic relationships.' Gene 304(1-2): 117-131. Rusten, T. E., K. Lindmo, G. Juhasz, M. Sass, P. O. Seglen, A. Brech and H. Stenmark (2004). 'Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway.' Dev Cell 7(2): 179-192. Sano, R. and J. C. Reed (2013). 'ER stress-induced cell death mechanisms.' Biochim Biophys Acta 1833(12): 3460-3470. Schultz, M. L., L. Tecedor, M. Chang and B. L. Davidson (2011). 'Clarifying lysosomal storage diseases.' Trends Neurosci 34(8): 401-410. Siddique, M. M., Y. Li, L. Wang, J. Ching, M. Mal, O. Ilkayeva, Y. J. Wu, B. H. Bay and S. A. Summers (2013). 'Ablation of dihydroceramide desaturase 1, a therapeutic target for the treatment of metabolic diseases, simultaneously stimulates anabolic and catabolic signaling.' Mol Cell Biol 33(11): 2353-2369. Siekhaus, D., M. Haesemeyer, O. Moffitt and R. Lehmann (2010). 'RhoL controls invasion and Rap1 localization during immune cell transmigration in Drosophila.' Nature Cell Biology 12(6): 605-610. Stenmark, H. and V. M. Olkkonen (2001). 'The Rab GTPase family.' Genome Biol 2(5): REVIEWS3007. Ternes, P., S. Franke, U. Zahringer, P. Sperling and E. Heinz (2002). 'Identification and characterization of a sphingolipid delta 4-desaturase family.' J Biol Chem 277(28): 25512- 25518. Uchiyama, Y., M. Koike, M. Shibata and M. Sasaki (2009). 'Autophagic neuron death.' Methods Enzymol 453: 33-51. Venken, K. J., K. L. Schulze, N. A. Haelterman, H. Pan, Y. He, M. Evans-Holm, J. W. Carlson, R. W. Levis, A. C. Spradling, R. A. Hoskins and H. J. Bellen (2011). 'MiMIC: a highly versatile transposon insertion resource for engineering Drosophila melanogaster genes.' Nat Methods 8(9): 737-743. Verhoeven, K., P. De Jonghe, K. Coen, N. Verpoorten, M. Auer-Grumbach, J. M. Kwon, D. FitzPatrick, E. Schmedding, E. De Vriendt, A. Jacobs, V. Van Gerwen, K. Wagner, H. P. Hartung and V. Timmerman (2003). 'Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy.' Am J Hum Genet 72(3): 722-727. Walls, S. M., Jr., S. J. Attle, G. B. Brulte, M. L. Walls, K. D. Finley, D. A. Chatfield, D. R. Herr and G. L. Harris (2013). 'Identification of sphingolipid metabolites that induce obesity via misregulation of appetite, caloric intake and fat storage in Drosophila.' PLoS Genet 9(12): e1003970. Yang, J. S., J. M. Bai and T. Lee (2008). 'Dynein-dynactin complex is essential for dendritic restriction of TM1-containing Drosophila Dscam.' PLoS ONE 3(10): e3504. Zhang, J., K. L. Schulze, P. R. Hiesinger, K. Suyama, S. Wang, M. Fish, M. Acar, R. A. Hoskins, H. J. Bellen and M. P. Scott (2007). 'Thirty-one flavors of Drosophila rab proteins.' Genetics 176(2): 1307-1322. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57482 | - |
| dc.description.abstract | Rab7 GTPase 為真核細胞中endolysosomal trafficking 重要調控者。人類Rab7
點突變會導致顯性遺傳的週邊神經退化症Charcot-Marie-Tooth 2B(CMT2B)。但目前 對其致病機轉尚未了解，而果蠅在rab7 序列高度保守及遺傳工具的便利，為我們研 究rab7 重要之模式動物。rab7 基因剔除果蠅在蛹晚期即死亡，其外觀和野生型(wild type)無異，但在死前腦中會有內體(endosome)堆積情形，且以eyFlp 在成蟲眼睛建立 缺少rab7 細胞並給予光照刺激後，其視神經之突觸傳遞功能幾乎消失，表示失去 rab7 會導致神經漸進性的喪失功能。 為更瞭解 rab7 造成神經退化之機制，我們以視神經之突觸傳遞功能為基礎， 使用異型合子(heterozygous) rab7 剔除果蠅進行大規模遺傳篩選。發現一基因infertile crescent (ifc)，不管是過度表現或是失去部分功能，都會惡化視神經突觸功能。ifc 乃 演化上高度保留之酵素，負責將dihydroceramide (DHC) 轉變成為神經醯胺(ceramide)。 而在ifc 失去功能下，果蠅會無法發育至成蟲並且有成蟲盤(imaginal discs)萎縮現象， 而在幼蟲時期，脂肪體(fat body)和眼盤(eye discs)則會有dihydroceramide 訊號堆積， 及內體(endosome)不正常分布情形。我們的研究除了確立rab7 及ifc 在果蠅神經系統 之中扮演的角色，也將intracellular membrane trafficking 和神經脂質(sphingolipid)之 平衡連結在一起，除對基因研究有貢獻外，或許也能藉改變神經脂質(sphingolipid)量 以達成治療神經退化疾病之願景。 | zh_TW |
| dc.description.abstract | The small GTPase Rab7 is a master regulator of endolysosomal traffickingin all
eukaryotic cells.In drosophila, loss of rab7 leads to lethality at late pupal stage with no gross morphologicalabnormalities. Whole-mount brain preparations of the rab7 null mutant in early pupal stages reveal substantial accumulations of the endosomal marker Hrs, indicating a defect in endolysosomal trafficking. Photoreceptors of newly hatched rab7 mutant initially function without obvious defects, as indicated in electroretinogram (ERG) recordings. In contrast, 5 day-old null mutant or 14 day-old heterozygous mutant, both raised under constant light stimulation, exhibit significant loss of synaptic function. To discover the mechanism underlying rab7-dependent synaptic transmission defects, we perform a modifier screen for rab7-interacting genes in Drosophila. Among 477 candidates, infertile crescent (ifc) is identified as a candidate which enhances the rab7- dependent synaptic transmission defects.Throughout evolution, infertile crescent is a highly conserved enzyme converting dihydroceramide into ceramide. In our study, we find that loss of ifc cause atrophy of imaginal discs and affect morphology and function of adult eye. In the larval stage, there are dihydroceramide signals accumulation and endosome abnormal distribution in fat body and eye discs.Taken together, our study has identifiedthe interaction of rab7 and ifc in Drosophila, and connects the intracellular membrane trafficking to sphingolipid metabolism. These findings not only add to genetic studies of rab7 and ifc but, with new perspectives on altering sphingolipid levels, shed light on potential therapeutic targets toward neurodegenerative diseases. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:48:00Z (GMT). No. of bitstreams: 1 ntu-103-R01441019-1.pdf: 1692731 bytes, checksum: c14492d022a97d6922b14b8f96f9bdb1 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 口試委員會審定書 .............................................................................................................................. i
誌謝 ..................................................................................................................................................... ii 摘要 ..................................................................................................................................................... iii Abstract ............................................................................................................................................... iv 第一章實驗背景 ................................................................................................................................ 2 1.1 神經細胞中膜狀胞器運輸機制和神經遺傳疾病關係........................................................... 3 1.3 dihyrdroceramide desaturase 於細胞與果蠅之功能............................................................... 5 第二章實驗材料與方法 .................................................................................................................... 8 2.1 果蠅株....................................................................................................................................... 9 2.2 果蠅食物培養基製備............................................................................................................. 11 2.3 基因轉殖果蠅製備................................................................................................................. 11 2.4 視神經電位紀錄(Electroretinogram) ..................................................................................... 13 2.5 免疫螢光染色(Immunohistochemistry) ................................................................................. 14 2.6 掃瞄式電子顯微鏡................................................................................................................. 15 2.7 即時聚合酶鏈式反應............................................................................................................. 15 第三章實驗結果 .............................................................................................................................. 17 3.1 在果蠅中，失去rab7 造成成蟲漸進性突觸功能喪失及視神經退化................................ 18 3.2 以異型合子rab7 剔除果蠅進行遺傳塞選以找出惡化感光細胞突觸功能基因................ 19 3.3 以rab7-Gal4 過度表現ifc-EP 會引起感覺神經突觸功能消失........................................... 19 3.4 rab7 和ifc 反式異型合子之感覺神經突觸功能消失........................................................... 20 3.5 失去ifc 造成幼蟲之成蟲盤(imaginal discs)萎縮，並且影響成蟲時眼睛型態和功能...... 20 3.6 失去ifc 造成發育期間之眼盤(eye discs)細胞死亡.............................................................. 21 3.7 失去ifc 導致dihydroceramide 堆積，並影響intracellular membrane trafficking .............. 22 第四章實驗討論 .............................................................................................................................. 23 4.1 失去rab7 後導致感光細胞之突觸功能漸進性受損............................................................ 24 4.2 探討rab7 遺傳相關基因dyn-p25、phae2 以及rapgap1 和rab7 可能之關係.................. 25 4.3 ifc 和rab7 共同調控感光細胞突觸功能............................................................................... 26 4.4 失去ifc 造成細胞死亡之可能機制....................................................................................... 26 ii 4.5 ifc 與intracellular membrane trafficking 之關係................................................................... 27 第五章未來實驗方向 ...................................................................................................................... 29 5.1 探討ifc 表現量失衡影響突觸功能之原因........................................................................... 30 5.2 探討失去 ifc 引起果蠅細胞死亡之機制.............................................................................. 30 5.2.1 確立dihydroceramide 增加會引起細胞死亡 ................................................................. 30 5.2.2 ifc-KG 突變果蠅引起細胞死亡之機制 .......................................................................... 31 5.2.3 失去ifc 對內質網(endoplasmic reticulum)功能之影響 ................................................. 32 第六章實驗圖表 .............................................................................................................................. 33 第七章參考文獻 .............................................................................................................................. 50 第八章附件 ...................................................................................................................................... 56 附件.1 在果蠅視覺神經失去rab7 會影響突觸功能並造成漸進性神經退化........................ 58 附件. 2 477 EP/EY 果蠅株表...................................................................................................... 59 | |
| dc.language.iso | zh-TW | |
| dc.subject | 果蠅 | zh_TW |
| dc.subject | 神經脂質 | zh_TW |
| dc.subject | 膜狀胞器運輸 | zh_TW |
| dc.subject | 細胞死亡 | zh_TW |
| dc.subject | sphingolipid | en |
| dc.subject | ifc | en |
| dc.subject | rab7 | en |
| dc.subject | Drosophila | en |
| dc.subject | cell death | en |
| dc.title | 探討rab7 遺傳相關基因ifc 於果蠅中對神經脂質平衡、
膜狀胞器運送及細胞死亡機制影響 | zh_TW |
| dc.title | The role of rab7-interacting gene, infertile crescent (ifc), in sphingolipid metabolism, endolysosomal trafficking and cell
death in Drosophila | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳君泰(June-Tai Wu),李秀香(Hsiu-Hsiang Lee),王培育(Pei-Yu Wang) | |
| dc.subject.keyword | 果蠅,神經脂質,膜狀胞器運輸,細胞死亡, | zh_TW |
| dc.subject.keyword | Drosophila,ifc,rab7,sphingolipid,cell death, | en |
| dc.relation.page | 70 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-07-25 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| 顯示於系所單位： | 生理學科所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-103-1.pdf 未授權公開取用 | 1.65 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。