三羧酸循環(Tricarboxylic acid cycle, TCA cycle)是生物體的基礎代謝途徑且同時扮演著調控體內平衡及壽命的重要角色。我們發現NIG9438R-1這株果蠅中CG32026表現有上升此外又有延長壽命的現象，而CG32026便是參與在果蠅TCA cycle中的的重要酵素－異檸檬酸脫氫酶(isocitrate dehydrogenase) 的一種相似基因，它可能可將異檸檬酸(isocitrate)代謝成α酮戊二酸(alpha-ketoglutarate)，而已經有報導指出在線蟲中餵給alpha-ketoglutarate，將會藉由抑制雷帕黴素靶蛋白(target of rapamycin, TOR)的路徑去延伸線蟲的壽命，然而並未有研究指出異檸檬酸脫氫酶在果蠅中是否也扮演著調控壽命及壓力耐受性的重要角色，因此在本篇論文，將以果蠅作為模式生物，證實異檸檬酸脫氫酶相似基因不僅可調控壽命，也影響飢餓、氧化性壓力的耐受性，此外，異檸檬酸脫氫酶相似基因CG32026的表現會負調控磷酸化S6激酶的表現，因而表明CG32026可能是藉由TOR的路徑去調控果蠅的壽命及壓力耐受性，總而言之，本篇論文證實了異檸檬酸脫氫酶相似基因CG32026可調控果蠅的壽命及壓力耐受性。

Tricarboxylic acid cycle (TCA cycle) is an essential metabolism pathway and plays an important role in homeostasis and lifespan regulation. We uncovered a mutant fly NIG 9438R-1 which displays extended lifespan and up-regulation of CG32026. CG32026 is predicted as isocitrate dehydrogenase-like gene, which may metabolize isocitrate to alpha-ketoglutarate in TCA cycle. Feeding of alpha-ketoglutarate has been reported to extend lifespan via TOR (target of rapamycin) pathway in C. elegans. It is not reported whether CG32026 plays a role in the regulation of lifespan and stress tolerance in Drosophila. Here, I demonstrated that knockdown of CG32026 (isocitrate dehydrogenase-like gene) might reduce lifespan and modulates starvation and oxidative tolerance in female flies. In addition, the expression of CG32026 negatively modulates the levels of the phosphorylated S6 kinase (p-S6K) in Drosophila, suggesting that the isocitrate dehydrogenase-mediated lifespan and stress tolerance may be involved in TOR pathway. Together, the data indicate that CG62026 isocitrate dehydrogenase-like gene regulates lifespan and stress tolerance in Drosophila.

Abstract i
中文摘要 ii
致謝 iii
Content 1
Introduction 2
Materials and Methods 7
Results 11
Conclusion and Discussion 17
Figures 20
Tables 41
Appendix 53
References 54

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