Functional Studies of Estrogen Related Receptors

项目摘要 代谢紊乱已成为全世界健康的日益沉重的负担， 肥胖和糖尿病的发病率。这些疾病对人类健康的影响重新关注生物医学 了解代谢调节的研究，目标是开发有效的新策略， 疗法这些努力之一集中在核受体（NRs）上，其是配体调节的大家族。 在发育、生长和代谢中起核心作用的转录因子。在Thummel实验室， 我们利用模型系统果蝇来发现NR调节的进化保守方面， 功能我的研究重点是雌激素相关受体（ERRs）在维持代谢稳态。 在小鼠和人类中，ERR家族由三种旁系同源物组成：ERRα、ERRβ和ERRγ。研究这些 受体在调节氧化磷酸化和线粒体功能中的重要性 在能量丰富的组织中。然而，我们对ERR功能的理解由于它们的重叠而变得复杂 表达模式、遗传冗余和补偿活动。此外，ERRα是脂质 然而，这种表型的组织特异性和机制基础都不清楚。 明白在果蝇中，ERR家族由一个直系同源物dERR代表，使我们能够研究ERR 在没有遗传冗余的情况下发挥作用。我的项目重点是定义dERR在 成年阶段的生活，当动物维持稳态的背景下，能量消耗，以支持 运动和繁殖的需求。我的初步研究表明，成年人dERR功能的丧失 导致生育力降低、糖原减少和几乎完全缺乏储存的甘油三酯。 通过RNA-seq进行的转录谱分析显示，许多参与脂质代谢的基因表达 在dERR突变体中降低水平。我的研究结果支持dERR维持成人脂质水平的假设 通过其在调节脂质合成和脂质转运中的作用。我将通过两个具体的例子来验证这个假设。 目的：（1）表征dERR的组织特异性功能;（2）检验dERR维持 脂质合成和转运。总之，这些研究利用了果蝇快速而强大的遗传学， 在没有功能冗余的情况下，定义ERR的祖先作用，提供新的见解， 哺乳动物受体已经多样化，以发挥其在代谢中的作用，并建立了理解的基础 ERR调节通路的错误调节如何导致代谢紊乱和人类疾病。

Project Summary Metabolic disorders have become an increasing burden for health worldwide as reflected by the unprecedented incidence of obesity and diabetes. The impact of these disorders on human health has refocused biomedical research on understanding the regulation of metabolism with a goal of developing new strategies for effective therapy. One of these efforts centers on nuclear receptors (NRs), which are a large family of ligand-regulated transcription factors that play central roles in development, growth and metabolism. In the Thummel laboratory, we utilize the model system Drosophila to discover evolutionarily-conserved aspects of NR regulation and function. My studies focus on the Estrogen-Related Receptors (ERRs) in maintaining metabolic homeostasis. Three paralogs make up the ERR family in mice and humans: ERRα, ERRβ, and ERRγ. Studies of these receptors have demonstrated their importance in regulating oxidative phosphorylation and mitochondrial function in energy-rich tissues. Our understanding of ERR functions, however, has been complicated by their overlapping expression patterns, genetic redundancy, and compensatory activities. Additionally, ERRα is necessary for lipid homeostasis in mammals; however, neither the tissue-specific nor mechanistic basis of this phenotype is well understood. In Drosophila, the ERR family is represented by a single ortholog, dERR, allowing us to study ERR functions in the absence of genetic redundancy. My project is focused on defining roles for dERR during the adult stage of life, when the animal maintains homeostasis in the context of energy expenditure to support the demands of motility and reproduction. My preliminary studies have shown that loss of dERR function in adults results in reduced fertility, decreased glycogen, and an almost complete lack of stored triglycerides. Transcriptional profiling by RNA-seq revealed that a number of genes involved in lipid metabolism are expressed at reduced levels in dERR mutants. My results support the hypothesis that dERR maintains lipid levels in adults through its roles in regulating lipid synthesis and lipid transport. I will test this hypothesis through two specific aims: (1) to characterize the tissue-specific functions of dERR and (2) to test the hypothesis that dERR maintains lipid synthesis and transport. Taken together, these studies exploit the rapid and powerful genetics of Drosophila to define the ancestral role of ERR in the absence of functional redundancy, provide new insights into how the mammalian receptors have diversified to exert their roles in metabolism, and establish a basis for understanding how misregulation of ERR-regulated pathways can contribute to metabolic disorders and human disease.