A Drosophila Model for the regulation of Aerobic Glycolysis

描述(申请人提供)：许多人类疾病的特点是新陈代谢的剧烈变化，这一观察结果在癌症中尤其明显，癌症中快速增殖的细胞变得高度依赖葡萄糖代谢。然而，癌细胞并不使用这种增加的糖酵解通量来产生能量，而是通过生物合成途径运送代谢中间产物，并通过产生乳酸来消除多余的丙酮酸。这种现象被称为有氧糖酵解或Warburg效应，允许癌细胞代谢大量葡萄糖，以产生细胞生长和增殖所需的生物量。癌细胞对葡萄糖代谢的依赖表明，这种代谢状态可以被用于治疗干预，并已成为癌症研究的焦点。我发现果蝇黑腹果蝇也利用有氧糖酵解来促进生长，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。我发现，发育调节的代谢开关发生在幼鱼生长开始之前，包括糖酵解、磷酸戊糖途径和乳酸产生的协调上调--这是有氧糖酵解的代谢标志。我建议使用这个程序化的发育事件作为一个模型系统，来剖析促进有氧糖酵解的遗传机制。我的初步研究已经被证明是成功的，因为我已经确定果蝇雌激素相关受体(DERR)是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，并为动物的快速生长做好准备。我还将确定DERR蛋白积累和激活的时间如何触发代谢切换到有氧糖酵解。此外，我会跟进观察到的情况 在癌细胞中，这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的角色改变。我推测，线粒体活动的这些变化为有效的生物质生产准备了细胞新陈代谢。 我将描述这些变化，并确定线粒体新陈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，变得依赖脂肪酸代谢。我将通过描述终止有氧糖酵解的保守遗传机制来探索第二个代谢转变--这是正常发育生长和癌症之间的关键区别。这些研究将首次在动物正常发育的背景下对有氧糖酵解的调节机制进行遗传解剖，并可能发现在新陈代谢水平上控制细胞生长的新方法。

DESCRIPTION (provided by applicant): 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.