A Drosophila Model for the Regulation of Aerobic Glycolysis

项目摘要 许多人类疾病的特征是新陈代谢发生巨大变化，这一观察结果是 在癌症中尤其明显，其中快速增殖的细胞变得高度依赖于葡萄糖 新陈代谢.然而，癌细胞并不利用糖酵解水平的增加来产生能量，而是利用糖酵解水平的增加来产生能量。 通过生物合成途径穿梭代谢中间产物，并依靠乳酸发酵来维持 高水平的糖酵解通量。这种现象被称为有氧糖酵解或瓦尔堡效应， 癌细胞代谢大量的葡萄糖以产生细胞生长所需的生物量 和扩散。癌细胞依赖于葡萄糖代谢的方式表明，这种代谢 国家可用于治疗干预，并已成为癌症研究的焦点。我有 发现果蝇Drosophila melanogaster也使用有氧糖酵解来促进生长， 建立了果蝇作为研究调节这种代谢的遗传机制的模型系统 程序.我最初使用这个模型的努力已经证明是成功的，因为我已经确定果蝇 雌激素相关受体（dERR）是有氧糖酵解的主要调节因子。我的实验室现在将扩展 这些初步的观察，以确定分子机制，既激活和抑制有氧 体内糖酵解。此外，我们已经确定，果蝇幼虫使用有氧糖酵解， 合成钉螺代谢产物L-2-羟基戊二酸（L-2 HG）。这种化合物几乎只在 癌症代谢的背景和L-2 HG的内源性作用仍然未被探索。我们将确定 如何在体内控制L-2 HG合成，并探索这种癌代谢物如何控制正常动物生长。 最后，我们将使用遗传学，基因组学和代谢组学的组合，以确定如何破坏 有氧糖酵解中的关键反应影响生长和生理。这些酶中的许多代表了潜在的 治疗目标和我们的创新方法提供了一个难得的机会，系统地评估 在整个动物系统中抑制单个糖酵解酶的作用。此外，我们的研究还探讨了 代偿性代谢途径，其响应于降低的糖酵解通量而被激活， 临床环境，可能使肿瘤对药物治疗不敏感。最后，我们发现了一个意想不到的 有氧糖酵解抑制、脂肪酸氧化水平增加和嘧啶之间的相关性 新陈代谢.我的实验室将利用这一意外的发现作为基础，探索人们所知甚少的 核苷酸生产中的脂肪酸β-氧化。我们的研究将第一次允许基因解剖 在正常动物发育的背景下调节有氧糖酵解的机制， 有可能揭示在代谢水平上控制细胞生长的新方法。

Project Summary 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 increased levels of glycolysis to generate energy, but rather shuttle metabolic intermediates through biosynthetic pathways and rely on lactate fermentation to maintain high levels of glycolytic flux. 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 manner in which cancer cells rely 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. My initial efforts using this model have proven successful, as I have determined that the Drosophila Estrogen-Related Receptor (dERR) is a master regulator of aerobic glycolysis. My lab will now expand upon these initial observations to identify the molecular mechanisms that both activate and repress aerobic glycolysis in vivo. Furthermore, we have determined that Drosophila larvae use aerobic glycolysis to synthesize the oncometabolite L-2-hydroxyglutarate (L-2HG). This compound is almost exclusively studied in the context of cancer metabolism and the endogenous roles of L-2HG remain unexplored. We will determine how L-2HG synthesis is controlled in vivo and explore how this oncometabolite controls normal animal growth. Finally, we will use a combination of genetics, genomics, and metabolomics to determine how the disruption of key reactions in aerobic glycolysis affects growth and physiology. Many of these enzymes represent potential therapuetic targets and our innovative approach provides a rare opportunity to systematically evaluate the effects of inhibiting individual glycolytic enzymes in a whole animal system. Moreover, our studies also explore the compensatory metabolic pathways that are activated in response to decreased glycolytic flux, which in a clinical setting, could render tumors insenstive to drug treatments. Finally, we have uncovered an unexpected correlation between the repression of aerobic glycolysis, increased levels of fatty acid oxidation, and pyrimidine metabolism. My lab will use this unexpected discovery as a foundation to explore the poorly understood role of fatty acid beta-oxidation in nucleotide production. Our 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.