A Drosophila Model for the regulation of Aerobic Glycolysis

项目摘要/摘要 许多人类疾病的特征是新陈代谢的戏剧性变化，这一观察到的是 尤其是在癌症中，快速增殖的细胞高度依赖葡萄糖。 新陈代谢。然而，癌细胞并不使用这种增加的糖酵解通量来产生能量，而是利用 在生物合成途径中穿梭代谢中间体，通过生产 乳酸盐。这种现象被称为有氧糖酵解或沃堡效应，使癌细胞能够 代谢大量葡萄糖，以产生细胞生长所需的生物量 扩散。癌细胞对葡萄糖代谢的依赖表明，这种代谢状态可能是 用于治疗干预，已成为癌症研究的焦点。我发现 果蝇也利用有氧酵解来促进生长，并建立了 果蝇作为研究调节这一代谢程序的遗传机制的模型系统。我 已经发现，发育调节的代谢开关发生在幼体发育开始之前， 包括糖酵解、磷酸戊糖途径和乳酸的协同上调 代谢产物--有氧糖酵解的新陈代谢特征。我建议使用这个程序 发育事件作为剖析促进有氧运动遗传机制的模型系统 糖酵解。我的初步研究已经被证明是成功的，因为我已经确定了果蝇的雌激素- 相关受体(DERR)作为这种代谢转换的关键调节因子。使用生物信息学方法，我将 确定代谢基因表达的协调变化如何建立有氧糖酵解和 为动物的快速成长做好准备。我还将确定DERR蛋白积累的时间和 激活会触发代谢切换到有氧糖酵解。此外，我将跟进观察到的情况 癌细胞，已表明有氧糖酵解的开始伴随着 有利于生物合成途径的线粒体酶。我推测线粒体的这些变化 活动为高效生产生物质准备细胞新陈代谢。我将描述这些变化，并 确定线粒体代谢如何与有氧糖酵解和发育生长相协调。 一旦幼虫生长完成，果蝇就会再次改变代谢状态，变得依赖脂肪酸 新陈代谢。我将通过描述保守的基因来探索第二次新陈代谢转变 终止有氧糖酵解的机制--正常发育生长和正常发育之间的关键区别 癌症。这些研究将首次对有氧运动的调节机制进行基因解剖。 糖酵解在正常动物发育的背景下，并可能发现新的方法来 在新陈代谢水平上控制细胞生长。

Project Summary/Abstract Many human diseases are characterized by dramatic changes in metabolism, an observation that is particularly evident in cancer, where rapidly proliferating cells become highly dependent on glucose metabolism. Cancer cells, however, do not use this increased glycolytic flux to generate energy but rather shuttle metabolic intermediates through biosynthetic pathways and eliminate excess pyruvate by producing lactate. This phenomenon, known as aerobic glycolysis or the Warburg effect, allows cancer cells to metabolize large quantities of glucose in order to generate the biomass required for cell growth and proliferation. The reliance of cancer cells on glucose metabolism suggests that this metabolic state could be exploited for therapeutic intervention, and has become a focal point in cancer research. I have discovered that the fruit fly Drosophila melanogaster also uses aerobic glycolysis to promote growth, and have established Drosophila as a model system for studying the genetic mechanisms that regulate this metabolic program. I have found that a developmentally-regulated metabolic switch occurs prior to the onset of juvenile growth, consisting of the coordinate up-regulation of glycolysis, the pentose phosphate pathway, and lactate production-a metabolic signature indicative of aerobic glycolysis. I propose to use this programmed developmental event as a model system for dissecting the genetic mechanisms that promote aerobic glycolysis. My initial studies have already proven successful, as I have identified the Drosophila Estrogen- Related Receptor (dERR) as a critical regulator of this metabolic switch. Using a bioinformatics approach, I will determine how coordinate changes in the expression of metabolic genes establish aerobic glycolysis and prepare animals for rapid growth. I will also determine how the timing of dERR protein accumulation and activation triggers the metabolic switch to aerobic glycolysis. Additionally, I will follow up on observations in cancer cells, which have shown that the onset of aerobic glycolysis is accompanied by altered roles for mitochondrial enzymes favoring biosynthetic pathways. I hypothesize that these alterations in mitochondrial activity prepare cellular metabolism for efficient biomass production. I will characterize these changes and determine how mitochondrial metabolism is coordinated with aerobic glycolysis and developmental growth. Once juvenile growth is complete, Drosophila again switches metabolic states to become reliant on fatty acid metabolism. I will explore this second metabolic transition by characterizing the conserved genetic mechanisms that terminate aerobic glycolysis-a critical distinction between normal developmental growth and cancer. These studies will allow, for the first time, a genetic dissection of the mechanisms regulating aerobic glycolysis within the context of normal animal development, and will potentially uncover novel approaches to control cellular growth at a metabolic level.