A Drosophila Model for the Regulation of Aerobic Glycolysis

项目摘要 Tennessen实验室使用果蝇作为模型来了解碳水化合物 代谢支持动物生长和发育的生物合成和能量需求。我们正在进行的 研究集中在称为瓦尔堡效应（有氧糖酵解）的代谢程序上。这个代谢程序 允许生长和增殖的细胞代谢大量的葡萄糖以产生生物质， 合成促生长信号分子。虽然有氧糖酵解通常与肿瘤有关， 在那里，它促进癌细胞、健康动物细胞如干细胞和激活的 T细胞也使用这种代谢程序来驱动生物合成并调节细胞命运决定。因此，基本 有氧糖酵解的研究不仅有可能确定可以靶向的代谢机制， 不仅能抑制肿瘤生长，还能揭示健康细胞如何操纵糖酵解代谢， 支持正常的发育生长。我发现果蝇也用 有氧糖酵解促进生长，并建立了苍蝇作为模型系统，用于研究遗传 调节这种代谢程序的机制。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）是有氧代谢的主要调节因子。 糖酵解我的实验室现在将扩大这些初步观察，以确定分子机制， 激活和抑制体内有氧糖酵解。此外，我们已经确定果蝇幼虫使用 有氧糖酵解合成癌代谢物L-2-羟基戊二酸（L-2 HG）。这个化合物几乎 在癌症代谢和内源性L-2 HG功能的背景下专门研究， 未开发的我们将确定L-2 HG的合成是如何在体内控制的，并探索这种致癌代谢物是如何在体内代谢的。 控制动物的正常生长最后，我们将结合遗传学、基因组学和代谢组学， 确定有氧糖酵解中关键反应的中断如何影响生长和生理。许多这些 酶代表了潜在的治疗靶点，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效果。 此外，我们的研究还探索了在响应于 糖酵解通量降低，这在临床环境中可使肿瘤对药物治疗不敏感。最后， 我们已经发现了有氧糖酵解的抑制， 脂肪酸氧化和嘧啶代谢。我的实验室将以这一意外发现为基础， 探索脂肪酸β-氧化在核苷酸生产中鲜为人知的作用。我们的研究将允许，因为 第一次，在正常的环境中调节有氧糖酵解的机制的遗传解剖， 动物发展，并将有可能发现新的方法来控制细胞生长在代谢水平。

Project Summary The Tennessen Lab uses the fruit fly, Drosophila melanogaster, as a model to understand how carbohydrate metabolism supports the biosynthetic and energetic demands of animal growth and development. Our ongoing studies focus on a metabolic program known as the Warburg effect (aerobic glycolysis). This metabolic program allows growing and proliferating cells to metabolize large quantities of glucose in order to generate biomass and synthesize pro-growth signaling molecules. While aerobic glycolysis is most commonly associated with tumors, where it promotes the growth and survival of cancer cells, healthy animal cells, such as stem cells and activated T cells, also use this metabolic program to drive biosynthesis and regulate cell fate decisions. Therefore, basic studies of aerobic glycolysis have the potential to not only identify metabolic mechanisms that could be targeted to inhibit tumor growth but also to reveal how healthy cells manipulate glycolytic metabolism as a means of supporting normal developmental growth. I have discovered that the fruit fly Drosophila melanogaster also uses aerobic glycolysis to promote growth and have established the fly 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 endogenous L-2HG function remains largely 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.