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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 | Yu-Han Yeh | en |
dc.contributor.author | 葉宇涵 | zh_TW |
dc.date.accessioned | 2021-06-17T04:39:51Z | - |
dc.date.available | 2028-07-10 | |
dc.date.copyright | 2018-09-06 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-08-06 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70823 | - |
dc.description.abstract | 神經磷脂質(Sphingolipid)為神經細胞膜之重要分子。在果蠅的神經磷脂質新合成路徑中,Infertile crescent (Ifc)為演化上具高度保守性的脂質修飾酵素–Dihydroceramide desaturase,具有轉化二羥基神經醯胺(dihydroceramide, DHCer)成神經醯胺(ceramide, Cer)的能力。之前實驗發現,在果蠅視神經失去ifc,會造成漸進式活性依賴退化、活性氧物質增加,以及細胞自噬活化的現象。
為探討活性氧物質的生成機制,前人在眼睛具有ifc-KO全感光細胞突變群組(ifc-KO whole eye clone)的果蠅的食物中餵食藥物apocynin去抑制NADPH oxidase (NOX),發現可以減緩視神經失去ifc所產生的神經退化。我利用ifc-KO感光細胞突變群組分析進而發現,Rac1在ifc-KO細胞中活化。同時,藉由視神經電位紀錄(electroretinogram)測試果蠅視神經的功能得知,在失去ifc的視神經中,再去抑制Rac1或是NOX,皆可部份恢復神經退化,因此我們認為Rac1-NOX為果蠅眼睛失去ifc之下,活性依賴退化及活性氧物種產生的途徑之一。為了進一步觀察Ifc和Rac1的關係,我藉由免疫共沉澱的方法發現兩者並沒有產生物理性交互作用,表示兩個蛋白的交互作用低於西方墨點法可檢測到的範圍,或是他們之間需要其他蛋白的溝通才能互相影響,須待進一步的實驗證明。 之前實驗發現,Ifc和Autophagosome 於視神經有共位的現象;同時,經由序列預測發現Ifc和autophagosome有四個可能產生連結的區域-LC3-interacting region (LIR)。因此我藉由免疫共沉澱的方法,進一步觀察兩者的關係,發現Ifc和autophagosome有產生物理性交互作用。另外,我們發現將同時突變四個LIRs的Ifc放回ifc-KO同型合子的果蠅時,無法拯救失去Ifc所造成的死亡。因此推論,存在於autophagosome的Ifc蛋白對果蠅的生存極為重要。 這些實驗結果支持:在果蠅視神經失去ifc,細胞會經由Rac1-NOX途徑產生活性氧物質及活性依賴退化。此外,存在於autophagosome的Ifc蛋白,對果蠅的生存有重大的影響。 | zh_TW |
dc.description.abstract | Sphingolipid is an essential component of cell membrane. Infertile crescent (Ifc) is an evolutionarily conserved dihydroceramide desaturase, which converts dihydroceramide to ceramide. Previously we have found that loss of ifc in Drosophila photoreceptors results in activity-dependent neurodegeneration, elevation of reactive oxygen species (ROS), and activation of autophagy.
To investigate the source of ROS, a NADPH oxidase (NOX)-specific inhibitor was fed to flies with ifc-KO photoreceptors. Apocynin-feeding reduced the level of ROS and partially rescued the neurodegeneration caused by loss of Ifc. Furthermore, with clonal analysis, we observe that Rac1 is activated in ifc-KO photoreceptors. Genetically decreasing the level of Rac1 or NOX partially rescued the function of the degenerated ifc-KO photoreceptors. These results indicate that Rac1-NOX pathway mediates ROS production which causes neurodegeneration in ifc-KO photoreceptors. We also used co-immunoprecipitation to detect the physical interaction between Rac1 and Ifc, but the interaction was not observed, indicating non-association or weak interaction between the two proteins. Interestingly, we have observed the colocalization of Ifc and autophagosome in the photoreceptor. With co-immunoprecipitation, we observed the physical interaction of Ifc and autophagosome. Also, Ifc is predicted to have four LC3-interactiong regions (LIRs) and Ifc with four mutated LIRs failed to rescue the lethality of ifc-KO flies, indicating the importance of Ifc to associate with autophagosomes. These results support that ROS and activity-dependent neurodegeneration is generated through Rac1-NOX pathway upon loss of Ifc in photoreceptors, and the ability of Ifc to interact with autophagosomes is critical for their survival. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T04:39:51Z (GMT). No. of bitstreams: 1 ntu-107-R05441009-1.pdf: 3309209 bytes, checksum: f4bb03fbe71f7318a635abe0d20b05e6 (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 謝辭 i
摘要 ii Abstract iv 目錄 v 第一章 實驗背景 1 1.1活性氧物質(Reactive Oxygen Species, ROS)的產生途徑 2 1.2 Rac1及NOX產生活性氧物質的途徑 4 1.3果蠅視神經的發育與維持以及活性依賴退化 8 第二章 實驗材料與方法 11 2.1 果蠅株及培養方法 12 2.2 果蠅食物培養基製備 13 2.3 視神經電位紀錄(Electroretinogram) 13 2.4 免疫螢光染色與共軛焦顯微鏡(Confocal microscope)使用 14 2.5 免疫染色抗體清單(IHC Antibody List) 16 2.6 群組分析(Clonal analysis) 16 2.7 免疫共沉澱 (co-immunoprecipitation, CO-IP) 17 2.8 果蠅蛋白萃取 17 2.9 西方墨點法(Western blotting) 18 第三章 實驗結果 20 3.1在果蠅視神經失去ifc導致Rac1活化 21 3.2在果蠅視神經失去ifc,同時抑制Rac1/NOX,可以部份恢復漸進式 神經退化 21 3.3 Ifc和Rac1沒有物理性交互作用(physical interaction) 22 3.4 Ifc和Autophagosome有物理性交互作用(physical interaction) 22 3.5在果蠅視神經失去ifc不影響Crumbs 23 3.6在果蠅眼睛過表達ifc可以部份恢復crumbs mutant經過光照所產生的神經退化 24 3.7經過光照的crumbs mutant果蠅眼睛有大量Ifc表現在細胞膜上 24 3.8經過十天光照的crumbs mutant果蠅眼睛沒有看到Rh1堆積,但觀察到autophagosomes大量表現在細胞膜上 25 3.9照光下,在果蠅視神經失去ifc造成Lamp表現量降低 26 3.10照光下,lysosomes功能在失去ifc的視神經中沒有變化 26 3.11照光下,在果蠅視神經失去ifc不影響細胞自噬的啟動與成熟 27 3.12 Ifc與Autophagosome之間的關係 27 第四章 實驗討論 30 4.1 Ifc調控Rac1可能的途徑 31 4.2 活性氧物質與細胞自噬間的連結 32 4.3 Ifc與細胞自噬的關係 33 4.4 探討ifc△(LTotal)-mCherry無法拯救失去ifc所造成的同型合子死亡的原 因 34 第五章 未來實驗方向 35 5.1 探討Ifc和Crumbs上下游關係 36 5.2 失去ifc之下,排除粒線體為ROS產生的來源 36 5.3 Ifc與Autophagosome的交互作用與ROS生成的關係 37 5.4 運用PLA(Proximity Ligation Assay)證明蛋白間的交互作用 37 第六章 實驗圖表 40 Fig. 1在果蠅視神經失去ifc導致Rac1活化 41 Fig. 2在果蠅視神經失去ifc,同時抑制Rac1/NOX,可以部份恢復漸進式 神經退化 42 Fig. 3 Ifc和Rac1沒有物理性交互作用(physical interaction) 43 Fig. 4 Ifc和Autophagosome有物理性交互作用(physical interaction) 44 Fig. 5在果蠅視神經失去ifc不影響Crumbs 45 Fig. 6在果蠅眼睛過表達ifc可以部份恢復crumbs mutant經過光照所產生的神經退化 46 Fig. 7經過光照的crumbs mutant果蠅眼睛有大量Ifc表現在細胞膜上 47 Fig. 8經過十天光照的crumbs mutant果蠅眼睛沒有看到Rh1堆積,但觀察到autophagosomes大量表現在細胞膜上 48 Fig. 9照光下,在果蠅視神經失去ifc造成Lamp表現量降低 49 Fig. 10照光下,lysosomes功能在失去ifc的視神經中沒有變化 50 Fig. 11照光下,在果蠅視神經失去ifc不影響細胞自噬的啟動與成熟 51 Table 1 Ifc△LIR Lethality Test 52 Fig.12 檢驗果蠅體內Ifc△LIR-mCherry的蛋白表現 53 第七章 參考文獻 54 | |
dc.language.iso | zh-TW | |
dc.title | Rac1-NOX途徑產生之活性氧物種於果蠅視神經調控
活性依賴神經退化之機制 | zh_TW |
dc.title | Rac1-NOX-dependent genesis of ROS mediates activity-dependent neurodegeneration in Drosophila photoreceptor | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳光超(Guang-Chao Chen),姚季光(Chi-Kuang Yao) | |
dc.subject.keyword | 果蠅,活性氧物種,神經退化, | zh_TW |
dc.subject.keyword | Drosophila,ROS,Neurodegeneration,Rac1-NOX, | en |
dc.relation.page | 60 | |
dc.identifier.doi | 10.6342/NTU201802488 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-08-07 | |
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 |
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