Translational regulation of PGC1alpha and oxidative metabolism

PGC1α 和氧化代谢的翻译调控

• 批准号: 10399645
• 负责人: Phillip Anthony Dumesic
• 金额: $ 9万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399645
• 关键词: 3' Untranslated Regions; Adipocytes; Adrenergic Agents; Affect; Affinity Chromatography; American; Area; Attention; Award; Basic Science; Biogenesis; Bioinformatics; Biotinylation; Case Study; Cell Respiration; Cells; Chemicals; Complement; Cytoplasmic Granules; Dana-Farber Cancer Institute; Data; Data Set; Diabetes Mellitus; Disease; Economic Burden; Elements; Energy Metabolism; Environment; Fatty acid glycerol esters; Fibrinogen; Follow-Up Studies; Foundations; Functional disorder; Gene Expression; Genetic Transcription; Genetic Translation; Goals; Health; Homeostasis; Hormones; Human; In Vitro; Instruction; Lead; Leadership; Mass Spectrum Analysis; Mentors; Mentorship; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Methods; Mitochondria; Molecular; Mus; Mutation; Norepinephrine; Obesity; Output; Oxidative Phosphorylation; Pathway interactions; Pharmacology; Phase; Phenotype; Physiological; Physiology; Play; Post-Transcriptional Regulation; Prevalence; Process; Property; Proteins; Proteomics; RNA; RNA-Binding Proteins; Regulation; Research; Ribosomes; Rodent Model; Role; Signal Transduction; System; Technology; Testing; Therapeutic; Thermogenesis; Tissues; Training; Translational Regulation; Translations; United States National Institutes of Health; Work; Writing; adipocyte biology; adipocyte differentiation; cell type; cis acting element; design; experimental study; genetic manipulation; helicase; hormone regulation; in vivo; insight; knock-down; medical schools; metabolic phenotype; mouse model; novel; obesity treatment; preference; prevent; programs; ribosome profiling; skills; stem; stress granule; transcriptomics; translation factor; translational impact; uncoupling protein 1

PROJECT SUMMARY As the prevalence of obesity and associated disorders rises, manipulation of adipocyte energy expenditure has gained attention as a potential means to treat metabolic disease. This strategy leverages the physiology of thermogenic adipocytes, a cell type that relies on oxidative phosphorylation metabolism to drive futile chemical cycles that release energy as heat. Recent work has suggested the potential for ribosomal control of thermogenic gene expression. Elucidating the responsible mechanisms may reveal novel means to manipulate adipocyte metabolism for the treatment of obesity and diabetes. This proposal tests the hypothesis that the distinct metabolism of thermogenic fat is enabled by specialized mRNA translation preferences inherent in this cell type. A first set of studies focuses on a single mRNA, PPARGC1A, and aims to purify the proteins that confer its cell-type-specific translational output. This mRNA encodes PGC1α, a dominant regulator of mitochondrial biogenesis. A second set of studies develops an in vivo mouse model to test the hypothesis that the helicase DDX3X, a regulator of mRNA translation and cytoplasmic stress granules, is a thermogenic-fat- selective translational regulator that supports expression of genes critical for oxidative metabolism. A third set of studies uses ribosome profiling technology to define the global mRNA translation dynamics associated with thermogenic activation. Together, these studies expand the scope of my work while generating foundational datasets and mouse models for my scientific independence. They will be carried out in the lab of a recognized leader in the field of molecular metabolism, Dr. Bruce Spiegelman, at the Dana-Farber Cancer Institute and Harvard Medical School. In this rich environment, I will benefit from a mentorship team committed to instruct me in: adipocyte biology, including in vivo genetic manipulation; mouse metabolic phenotyping; mass spectrometry; and bioinformatics. The technical training is complemented by formal instruction in human metabolic pathophysiology, as well as activities for honing my leadership, speaking, and writing skills. In this way the NIH Pathway to Independence Award supports my transition from mentored work to an independent stage in which I intend to use cutting-edge methods to broadly define the translational dynamics of thermogenic fat, identify the responsible regulators, and test how post-transcriptional dynamics such as stress granule assembly may contribute. My ultimate goal is to lead an academic research group that investigates how the gene expression programs that define cellular identity and metabolism are established, how they are perturbed in metabolic disease, and how they may be therapeutically manipulated to prevent or treat metabolic disease.

项目摘要 随着肥胖症和相关疾病的患病率的增加，对脂肪的操纵已经具有 作为治疗代谢疾病的潜在手段。 热脂肪细胞，一种依赖氧化磷酸化代谢的细胞类型 释放能量作为热量的周期提出了核糖体控制的可能性 热基因表达。 脂肪细胞代谢治疗肥胖和糖尿病。 热脂肪脂肪的独特代谢是由专门的mRNA翻译偏好赋予的。 细胞类型。 赋予其细胞类型的转换输出。 线粒体生物发生。 解旋酶DDX3X是mRNA翻译和细胞质应激颗粒的常规者，是一种热脂肪 - 选择性翻译调节剂支持氧化代谢的基因表达。 研究使用核糖体分析技术来定义与之相关的全局mRNA翻译动力学。 热激活，这些研究扩大了我的工作范围 我的科学独立性的数据集和鼠标模型将在公认的实验室中进行 分子代谢领域的领导者布鲁斯·斯皮格曼（Bruce spiegelman 哈佛医学院。 我在：脂肪细胞生物学，包括体内遗传操作； 光谱和生物信息学。 代谢性病理生理学，以及磨练我的领导力，讲话和写作技巧的活动 NIH独立奖的方式支持我从指导工作到独立的过渡 我打算使用尖端方法来广泛定义的翻译动力学的阶段 热脂肪，识别响应调节剂并测试转录后动态如何这样的助手 颗粒组件可能会做出贡献。 如何确定细胞身份和代谢的基因表达程序如何 在代谢疾病中受到干扰，以及如何在治疗上操纵以预见一些 疾病。