Ribosome biogenesis regulates adipocyte function

核糖体生物发生调节脂肪细胞功能

• 批准号: 9761518
• 负责人: Libin Liu
• 金额: $ 41.25万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761518
• 关键词: Adipocytes; Adipose tissue; Animal Model; Biogenesis; Biological Markers; Caveolae; Cell Culture Techniques; Cell Line; Cell Nucleus; Cell physiology; Cell surface; Characteristics; Confusion; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Diagnostic; Dominant-Negative Mutation; Ensure; Etiology; Event; Fasting; Functional disorder; Genetic Transcription; Homeostasis; Human; In Vitro; Individual; Insulin; Insulin Resistance; Lead; Light; Lipids; Lipodystrophy; Maintenance; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic stress; Metabolic syndrome; Modeling; Modification; Molecular; Monoubiquitination; Mutation; Names; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Export; Nuclear Localization Signal; Nuclear Translocation; Nutrient; Obesity; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Physiology; Play; Polymerase; Post-Translational Protein Processing; Process; Protein Biosynthesis; Proteins; Quality Control; RNA chemical synthesis; Recombinant DNA; Regulation; Regulatory Pathway; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; Serine; Signal Pathway; Signal Transduction; Site; Starvation; Testing; Therapeutic; Threonine; Transcript; Transcriptional Regulation; Transgenic Mice; Tyrosine; Work; adipokines; biological adaptation to stress; genome editing; hormone regulation; improved; in vitro Model; in vitro activity; in vivo; insulin sensitivity; interest; mouse model; novel therapeutic intervention; nucleocytoplasmic transport; obesity risk; preservation; release factor; response; ribosome releasing factor; therapeutic target

Project Summary Dysfunctional white adipose tissue (WAT) plays a central role in the etiology of metabolic disorders including diabetes and metabolic syndromes. However, not all obese adipose tissue is necessarily associated with pathological changes. Individuals seem to have a functional set limit beyond which WAT fails to function properly. Identification of such mechanisms or factors that control the set point is of great interest. Given the importance of a homeostatic protein synthesis as a basic cellular function, it is postulated that the healthy adipocyte's functional regulation should also incorporate allostatic adaptions of protein synthesis aiming to maintain larger cellular body and adipokine secretion demands as long as possible, particularly under metabolically challenging conditions. In this proposal it is hypothesized that the capacity of adaptational ribosome biogenesis may determine the maximal limit of adipocyte functional homeostasis. PTRF (Cavin-1) was original cloned as "polymerase I and transcription release factor". The preliminary data here show PTRF functionally localizing in the nucleus and playing a critical role on the regulation of ribosomal DNA transcription efficiency. To study the details of molecular mechanisms, 3 aims are proposed: Aim-1, to define the PTRF, ribosome biogenesis and adipocyte function regulatory pathway; Aim-2, to understand how this pathway regulates the cellular localization of PTRF; and Aim-3, to explore the physiological relevance of these observations. By using comprehensive cell culture and mouse models, the studies from this proposal will not only shed light on the molecular mechanistic details of this regulatory pathway but also provide potential therapeutic targets for improving adipocyte homeostasis and quality control in human obesity and diabetes.

项目摘要 功能失调的白色脂肪组织（WAT）在代谢紊乱的病因学中起着核心作用 包括糖尿病和代谢综合征。然而，并不是所有的肥胖脂肪组织都必须 与病理变化有关。个人似乎有一个功能设定的限制，超过这个限制， 无法正常工作。识别控制设定点的这种机制或因素是非常重要的 兴趣鉴于稳态蛋白质合成作为基本细胞功能的重要性， 健康的脂肪细胞的功能调节也应该包括蛋白质的非稳态适应， 旨在维持较大细胞体和脂肪因子分泌的合成需要尽可能长的时间， 特别是在代谢挑战条件下。在该提案中，假设容量 适应性核糖体生物合成的能力可能决定脂肪细胞功能稳态的最大限度。 PTRF（Cavin-1）最初克隆为“聚合酶I和转录释放因子”。初步数据 PTRF功能定位于细胞核，在调节细胞凋亡中起关键作用。 核糖体DNA转录效率。为了研究分子机制的细节，提出了3个目标： 目的-1，明确PTRF、核糖体生物合成和脂肪细胞功能调控途径;目的-2， 了解该途径如何调节PTRF的细胞定位; Aim-3，探索PTRF的细胞定位。 这些观察结果的生理相关性。通过使用全面的细胞培养和小鼠模型， 这项提议的研究不仅将揭示这种调节的分子机制细节， 而且还提供了改善脂肪细胞稳态和质量的潜在治疗靶点 控制人类肥胖和糖尿病。