A Drosophila Model for the regulation of Aerobic Glycolysis

调节有氧糖酵解的果蝇模型

• 批准号: 8788539
• 负责人: Jason Michael Tennessen
• 金额: $ 24.64万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788539
• 关键词: Acetylation; Adolescent; Animals; Biochemical; Bioinformatics; Biological Models; Biomass; Cancer Cell Growth; Cataloging; Catalogs; Cell Proliferation; Cells; Citric Acid Cycle; Complex; Data; Development; Dissection; Down-Regulation; Drosophila genus; Drosophila melanogaster; EGF gene; Ecdysterone; Electron Transport; Enzymes; Event; Family member; Gene Expression; Genes; Genetic; Genetic Models; Genetic study; Glucose; Glycolysis; Goals; Growth; Insulin; Isotopes; Laboratories; Larva; Malignant Neoplasms; Maps; Measures; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Modification; Molecular; Morphology; Nuclear Receptors; Pathway interactions; Pentosephosphate Pathway; Phase; Phosphorylation; Post-Transcriptional Regulation; Production; Proliferating; Proteomics; Pyruvate; Regulation; Research; Respiration; Role; Signal Pathway; Study models; Testing; Therapeutic Intervention; Time; Tracer; Training; Up-Regulation; Warburg Effect; abstracting; aerobic glycolysis; anticancer research; cancer cell; cancer therapy; career development; cell growth; enzyme activity; estrogen-related receptor; fatty acid metabolism; follow-up; genetic approach; genome-wide; glucose metabolism; human ERD5 protein; human disease; innovation; novel; novel strategies; programs; rapid growth; receptor; skills; steroid hormone; tumor growth; tumor progression

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.

项目总结/摘要 许多人类疾病的特征是新陈代谢的急剧变化，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，癌细胞并不利用这种增加的糖酵解通量来产生能量，而是利用这种增加的糖酵解通量来产生能量。 通过生物合成途径穿梭代谢中间产物，并通过产生 乳酸盐这种现象，被称为有氧糖酵解或瓦尔堡效应，使癌细胞， 代谢大量葡萄糖以产生细胞生长所需的生物质， 增殖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，并已成为癌症研究的焦点。我发现 果蝇Drosophilamelanogaster也使用有氧糖酵解来促进生长，并已经建立了 果蝇作为研究调节这种代谢程序的遗传机制的模型系统。我 发现发育调节的代谢转换发生在幼年生长开始之前， 包括糖酵解、戊糖磷酸途径和乳酸的协调上调 产生-指示有氧糖酵解的代谢特征。我建议用这个程序 发育事件作为一个模型系统解剖的遗传机制，促进有氧 糖酵解我的初步研究已经证明是成功的，因为我已经确定了果蝇雌激素- 相关受体（dERR）作为这一代谢开关的关键调节因子。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， 让动物快速成长。我还将确定dERR蛋白积累的时间， 激活触发代谢转换为有氧糖酵解。此外，我还将对下列意见采取后续行动： 癌细胞，这表明有氧糖酵解的开始伴随着改变的作用， 线粒体酶有利于生物合成途径。我推测这些线粒体的改变 活性为有效的生物质生产准备细胞代谢。我将描述这些变化， 确定线粒体代谢如何与有氧糖酵解和发育生长协调。 一旦幼年期生长完成，果蝇再次转换代谢状态，变得依赖脂肪酸 新陈代谢.我将通过描述保守的遗传基因来探索这第二次代谢转变， 终止有氧糖酵解的机制-正常发育生长和 癌这些研究将首次允许对有氧代谢调节机制进行遗传解剖。 糖酵解在正常动物发育的背景下，并可能揭示新的方法， 在代谢水平上控制细胞生长。