A Drosophila Model for the regulation of Aerobic Glycolysis

调节有氧糖酵解的果蝇模型

• 批准号: 8279968
• 负责人: Jason Michael Tennessen
• 金额: $ 8.99万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279968
• 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; 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; Reliance; Research; Respiration; Role; Signal Pathway; Study models; Testing; Therapeutic Intervention; Time; Tracer; Training; Up-Regulation; Warburg Effect; aerobic glycolysis; anticancer research; cancer cell; cancer therapy; career development; cell growth; enzyme activity; estrogen-related receptor; fatty acid metabolism; follow-up; genome-wide; glucose metabolism; human ERD5 protein; human disease; innovation; novel; novel strategies; programs; rapid growth; receptor; skills; steroid hormone; tumor growth; tumor progression

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. PUBLIC HEALTH RELEVANCE: Cancer cell growth and proliferation requires a unique form of metabolism called aerobic glycolysis. Recent studies indicate that disrupting aerobic glycolysis can inhibit tumor growth. This project uses the fruit fly Drosophila melanogaster, as a genetic model for studying the mechanisms that control aerobic glycolysis with the goal of identifying possible new approaches to cancer treatment.

描述（由申请人提供）：许多人类疾病的特征是代谢的剧烈变化，这在癌症中尤其明显，其中快速增殖的细胞高度依赖于葡萄糖代谢。然而，癌细胞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体，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，它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（Drosophila melanogaster）也使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、戊糖磷酸途径和乳酸生成的协调上调——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）是这种代谢开关的关键调节器。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转换为有氧糖酵解。此外，我会跟进观察结果