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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 詹智強(Chih-Chiang Chan) | |
| dc.contributor.author | Chung-Chih Liu | en |
| dc.contributor.author | 劉中致 | zh_TW |
| dc.date.accessioned | 2021-06-16T02:50:57Z | - |
| dc.date.available | 2020-09-25 | |
| dc.date.copyright | 2015-09-25 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-07-14 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54332 | - |
| dc.description.abstract | Rab7 GTPase為真核細胞之內溶酶體運輸(endolysosomal trafficking)和細胞自噬作用(autophagy)的重要調控蛋白，人類Rab7點突變會造成顯性遺傳的週邊神經退化症Charcot-Marie-Tooth 2B (CMT2B)，但目前其致病機轉尚未明瞭，為釐清其致病機轉，我們建立了第一套CMT2B之果蠅動物模式。我們的研究指出Rab7失去被召集至內體(endosomal recruitment)之能力是神經突觸功能喪失進而導致退化之主因。 為瞭解rab7依賴性神經退化之機制，我們以rab7基因剔除之異型合子果蠅進行遺傳篩選，發現一基因infertile crescent (ifc)無論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為演化上具高度保守性的脂質修飾酵素，負責將dihydroceramide (DHC)轉變成神經醯胺(ceramide)。而在ifc部分失去功能下(ifc-KG突變體)，果蠅會於二齡幼蟲時死亡且會導致發育時期神經死亡，但應非經由細胞凋亡(apoptosis)或內質網壓力(ER stress)途徑。由於Rab7主要調控內溶酶體融合(endolysosomal fusion)及自噬小體成熟(autophagosomal maturation)，我們進而檢測ifc是否亦參與調控細胞自噬作用(autophagy)。活體過表達或是抑制ifc表現皆會改變細胞自噬蛋白ATG8/LC3-mcherry及攜帶蛋白Ref(2)P/p62的分布，而在ifc失去功能下，細胞中的磷酸化JNK有提升的現象，前人研究發現磷酸化JNK參與調控細胞自噬細胞死亡(Shimizu, Konishi et al. 2010)，推測Ifc可能參與經由細胞自噬造成細胞死亡之途徑。ifc喪失部分功能亦會提高溶酶體(lysosome)分解物質的能力及提升Rab7的蛋白表現量。此外我們亦發現於眼睛建立ifc-KO(完全失去ifc)突變細胞群組(mutant clone)並沒有發育上的缺失，而會導致成體漸進的視神經退化。 我們的研究除了瞭解ifc於神經發育及神經退化中扮演的角色，也將神經脂質(sphingolipid)平衡及細胞自噬作用連結在一起，除對rab7之作用機轉更加瞭解外，或許也能作為周邊神經退化患者可能療法的理論基礎。 | zh_TW |
| dc.description.abstract | The small GTPase Rab7 is a master regulator of endolysosomal trafficking and autophagy in all eukaryotic cells. Various mutations of rab7 are linked with the dominant neuropathy Charcot-Marie-Tooth 2B (CMT2B). To investigate the molecular mechanism underlying CMT2B, we established the first animal model for CMT2B, and suggested that the adult-onset synaptic defect and subsequent neurodegeneration result from partial loss of rab7 function. From a genetic screen for rab7-interacting genes, we identify infertile crescent (ifc) as a potential suppressor which overexpression promotes the degenerative defects caused by heterozygous rab7 mutant. Ifc is an evolutionarily conserved lipid-modifying enzyme that converts dihydroceramide (DHC) into ceramide. Our results indicate loss of ifc leads to developmental neuronal loss that is unlikely caused by apoptosis or ER stress. Interestingly, both overexpression and loss of function of ifc results in altered subcellular patterns of ATG8/LC3-mcherry and Ref(2)P/p62, moreover, loss of ifc leads to pJNK elevation in neurons suggesting the regulation by Ifc in autophagic cell death. Interestingly, loss of ifc enhances lysosomal degradative capacity and Rab7 protein level. Furthermore, we used the FLP/FRT system to induce homozygous ifc-KO mutant clones in the photoreceptor neurons and found adult usage-dependent neurodegeneration instead of developmental defects in the eye. We seek to understand the role of ifc on the neuronal development and degeneration, which potentially will shed light on the therapeutic approaches for patients with peripheral neuropathy. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T02:50:57Z (GMT). No. of bitstreams: 1 ntu-104-R02441004-1.pdf: 8549390 bytes, checksum: 1cef55b186b6b084c772e8e2f6ccb054 (MD5) Previous issue date: 2015 | 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 4 1.1 神經細胞中膜狀胞器運輸機制和神經遺傳疾病關係 5 1.2 Rab7功能及Charcot-Marie-Tooth type 2B神經病變 6 1.3 神經脂質新合成路徑(Sphingolipid De novo pathway)調控神經發育及神經退化 8 1.4 Dihydroceramide Desaturase於哺乳類細胞及果蠅中之功能 11 1.5 Ceramide和 Dihydroceramide於細胞自噬作用中所扮演之角色 13 第二章 實驗材料與方法 15 2.1 果蠅株 16 2.2 果蠅食物培養基製備 18 2.3 視神經電位紀錄(Electroretinogram) 18 2.4 免疫螢光染色(Immunohistochemistry) 19 2.5 掃瞄式電子顯微鏡 20 2.6 免疫染色抗體清單(IHC Antibody List) 21 2.7 西方墨點法(Western blotting) 22 2.8 ifc基因剃除(gene knockout)果蠅製作 23 2.9 群組分析(Clonal analysis) 24 2.10即時聚合酶鏈式反應(Real-Time Quantitative PCR) 24 第三章 實驗結果 27 3.1 以異型合子rab7剔除果蠅進行遺傳篩選確認ifc為rab7依賴性神經退化的強化子(enhancer) 28 3.2 失去ifc導致果蠅眼睛發育上及功能上的缺失 28 3.3 失去ifc會在發育階段導致視神經細胞死亡 29 3.4 ifc調控神經發育應不經由細胞凋亡(apoptosis)或是內質網壓力(ER stress)訊息傳導路徑 29 3.5 於視神經細胞部分失去ifc會提升溶酶體分解能力(lysosomal degradative capacity) 30 3.6 Ifc調控細胞自噬作用 31 3.7 過表達Ifc及DEGS1導致Tau神經毒性(Tau neurotoxicity)增加 32 3.8 於視神經細胞中過表達Ifc會抑制過表達Atg1所調控的細胞死亡(Atg1-induced cell death) 32 3.9 ifc基因剃除(gene knockout)果蠅呈現發育遲緩現象 33 3.10 在果蠅中，完全失去ifc導致成蟲漸進性突觸功能喪失及視神經細胞退化 33 3.11失去ifc會造成Rab7蛋白質表現量增加 33 3.12失去ifc會造成細胞自噬作用相關基因(autophagy related genes)表現量增加 33 第四章 實驗討論 35 4.1 ifc-KG與ifc-KO兩ifc突變體表現型(phenotype)之異同比較 36 4.2 失去ifc造成細胞死亡之可能機制 36 4.3 過表達ifc或失去ifc影響細胞自噬作用之可能機制 38 4.4 ifc於神經細胞及神經膠細胞(glial cell)扮演重要角色 38 4.5 Ifc與Rab7可能之關係 38 第五章 未來實驗方向 40 5.1探討失去ifc引起細胞於發育過程中死亡之原因 41 5.2 探討失去ifc導致視神經退化之機制 42 5.3探討ifc-KO與ifc-KG兩突變體其表現型不同之原因 42 5.4探討Ifc與Rab7之間的關係 43 第六章 實驗圖表 44 第七章 參考文獻 89 | |
| dc.language.iso | zh-TW | |
| dc.subject | 神經脂質 | zh_TW |
| dc.subject | 神經退化 | zh_TW |
| dc.subject | 細胞自噬作用 | zh_TW |
| dc.subject | 細胞自噬作用 | zh_TW |
| dc.subject | 神經發育 | zh_TW |
| dc.subject | 神經退化 | zh_TW |
| dc.subject | 神經脂質 | zh_TW |
| dc.subject | 神經發育 | zh_TW |
| dc.subject | neuronal degeneration | en |
| dc.subject | infertile crescent | en |
| dc.subject | autophagy | en |
| dc.subject | dihydroceramide | en |
| dc.subject | neuronal development | en |
| dc.subject | neuronal degeneration | en |
| dc.subject | infertile crescent | en |
| dc.subject | autophagy | en |
| dc.subject | dihydroceramide | en |
| dc.subject | neuronal development | en |
| dc.title | infertile crescent (ifc) 於神經發育及神經退化中調控細胞自噬作用 | zh_TW |
| dc.title | infertile crescent (ifc) regulates autophagy in both neuronal development and degeneration | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳俊宏(Chun-Hong Chen),姚季光(Chi-Kuang Yao),陳光超(Guang-Chao Chen) | |
| dc.subject.keyword | 神經脂質,細胞自噬作用,神經發育,神經退化, | zh_TW |
| dc.subject.keyword | infertile crescent,autophagy,dihydroceramide,neuronal development,neuronal degeneration, | en |
| dc.relation.page | 95 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-07-14 | |
| 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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