臺灣博碩士論文加值系統

神經鞘脂質 (sphingolipids) 家族成員十分複雜，兼具形成細胞膜結構與訊號傳遞功能角色。而神經鞘磷脂 (sphingomyelin，SM) 為細胞脂雙層主要結構一員，更富含於脂筏 (rafts) 中，神經鞘磷脂合成與代謝中樞分子神經醯胺 (ceramide) ，為sphingomyelin之前驅物，除ceramide外，家族成員中如sphingosine、sphingosine 1-phosphate (S1P) 及gangliosides 等皆具生物活性，能影響細胞分化、增生、凋亡等。過去研究顯示黴菌伏馬鐮孢毒素 (Fumonisin B1, FB1) 會抑制神經醯胺合成酶 (ceramide synthase ; CerS) 活性，進而干擾神經磷脂質之代謝，並且影響細胞功能。然而其毒理機制卻未盡周詳，故本研究以肌肉細胞為模式，探討干擾神經醯胺合成酶影響生肌作用之機制。生肌作用分化過程 (myogenic differentiation) 包括肌肉專一基因的表達、細胞形態延展成梭狀，而後遷徙、列隊 (alignment) 進一步相互融合成多核肌纖維 (myofibers)。其中細胞骨架的重整參與這一系列的過程，膜上的脂筏與蛋白質的分布亦會隨分化過程而改變。
研究結果顯示:sphingomyelinase抑制劑GW4869，會抑制C2C12細胞分化；加入外源性的sphingomyelin並不會影響細胞分化；然而加入ganglioside GM3 或 S1P則會促進細胞分化，並抵銷 FB1 對分化的抑制效果，有效挽救細胞分化。基因上利用Longevity assurance genes 1 (LASS1) siRNA干擾神經醯胺合成酶，而藥理上以FB1 抑制其活性，結果顯示:LASS1 siRNA與FB1干擾皆會造成ceramide含量下降，令人驚訝的是， LASS1 siRNA 促進細胞分化； 而FB1 則為抑制效果。細胞內其他的神經鞘脂質如 sphingomyelin ， 其含量在 LASS1 siRNA與 FB1 處理下皆稍微降低，而 LASS1 siRNA 以及FB1處理皆會增加 sphingosine 含量。另外測定 IGF-I的含量發現，以 FB1 處理顯著抑制 IGF-I 的分泌，而相反的，LASS1 siRNA對IGF-I的分泌則是促進的效果。細胞形態上顯示: LASS1 siRNA 和SMS2 overexpression處理皆增強細胞骨架集中附著點 (focal adhesions) ，而以SMS2 (sphingomyelin synthase 2) siRNA干擾 sphingomyelin 合成，則會抑制 focal adhesions。以 LASS1 siRNA 干擾或經SMS2 overexpression的細胞其遷徙能力顯著增加；而 FB1、SMS2 siRNA、D609 (SMS inhibitor) 處理則顯著降低細胞遷徙能力。接著以 CTxB (cholera toxin subunit B) 標識細胞膜脂筏，再以 time lapse 下追蹤，結果顯示:細胞膜上富含 sphingolipids 之脂筏主要分佈於細胞間接觸邊緣，在分化時會往細胞前後兩端聚集。脂筏移動可導致漿膜脂雙層小區域物化特性改變，在區域環境內能幫助細胞往同方向進行移動、排列與融合。綜合以上結果，調控神經鞘脂質代謝中的 ceramide synthase ，會影響其上下游代謝物含量，進而影響細胞膜脂筏形成與細胞骨架重整 (remodeling)，接著進一步影響細胞遷徙、排列與融合等過程，而最終影響細胞分化。

1. 前言………………………………………………………………………………….1
2. 文獻探討…………………………………………………………………………….2
2.1. 生肌作用 (Myogenesis) ....................................................................................2
2.1.1. 骨骼肌 (Skeletal muscle)………………………………...4
2.1.2. 肌纖維 (Myofibers)……………………………………5
2.1.3. 細胞骨架 (Cytoskeleton) ………………………………..6
2.1.4. 衛星細胞 (Satellite cells) ………………………………………..7
2.2. 生肌作用之訊號傳遞………………………………………………………….8
2.2.1. 生肌作用的正調控 (Positive Signaling Pathways of Myogenesis)…10
2.2.2. 生肌作用的負調控 (Negative Signaling Pathways of Myogenesis)..11
2.2.3. 細胞內IGF-I 訊號傳遞 (Intracellular IGF-I signaling)………………11
2.3. 細胞膜與脂肪區域…………………………………………………………13
2.3.1. 脂筏 (Lipid rafts) ……………………………………………………13
2.4. 神經鞘脂質 (Sphingolipids) ………………………………………14
2.4.1. 神經鞘脂質之代謝 (Sphingolipids metabolism) ……………………15
2.4.2. 神經鞘磷脂 (Sphingomyelin) ………………………………16
2.4.3. 神經節苷脂 (Ganglioside) ………………..………….17
2.4.4. 神經醯胺 (Ceramide) …………………………………………………18
2.5. 黴菌伏馬鐮孢毒素 (Fumonisin B1) ………………………………………21
2.6. 總結…………………………………………………………………………23
2.7. 研究目標……………………………………………………………………24
3. 材料方法…………………………………………………………………………25
3.1. 細胞培養 (Cell culture) ……………………………………………25
3.2. 化學藥劑處理 (Chemical treatments) ……………………………………25
3.3. 西方西漬法 (Western blot analysis) …………………………………25
3.4. 細胞遷移 (Migration assay) …………………………………………………26
3.5. 免疫螢光染色法 (Immunofluorescence staining) ………………………27
3.6. 短干擾性RNA處理 (Short interfering RNA intervention) …………………27
3.7. 細胞脂肪含量測定 (Cellular lipid content) ………………………………27
3.8. 神經鞘磷脂含量測定 (Sphingomyelin content) ……………………………28
3.9. 即時影像 (Time-lapse) ……………………………………………………28
3.10. IGF-I ELISA測定 (IGF-I ELISA) ………………………………………29
3.11. 統計分析 (Statical analysis) ………………………………………………29
4. 結果………………………………………………………………………………30
4.1. 神經鞘脂質成員對於機緣細胞分化之影響………………………………30
4.2. 抑制神經醯胺合成酶對於肌原母細胞分化、遷徙及分化指標蛋白表現之影 響………………………………………………………………………………33
4.3. 干擾神經鞘脂質途徑對於細胞中各脂質成員含量的影響………………..37
4.4. FB1干擾神經醯胺合成酶對IGF-I 訊號傳遞途徑的影響……………..40
4.5. 基因操作干擾神經醯胺合成酶與神經鞘磷脂合成酶影響肌原母細胞之細 胞集中附著點…………………………………………………………………42
4.6. 藉基因操作提升神經鞘磷脂合成酶表現………………………………48
4.7. 藉由藥理上抑制劑D609與基因操作調控神經鞘磷脂合成酶活性對於肌原母細胞遷徙之影響……………………………………………………………50
4.8. 肌原母細胞分化時期脂筏移動之情形…………………………………54
5. 討論……………………………………………………………………………57
5.1. 神經鞘脂質成員對於肌原母細胞分化之影響……………………………57
5.2. 細胞膜上脂筏之移動以及細胞骨架附著點………………………………58
5.3. 經醯胺合成酶活性對肌原母細胞分化及融合之影響……………………59
5.4. Fumonisin B1與LASS1 siRNA造成細胞分化不同結果之探討…………61
5.5. 總結…………………………………………………………………………62
6. 結論…………………………………………………………………………...…64
7. 參考文獻……………………………………………………………………...……65

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