Deciphering the extra-telomeric function of Rap1, a metabolic regulator counterac

破译代谢调节因子 Rap1 的端粒外功能

• 批准号: 8749789
• 负责人: Agnel Sfeir
• 金额: $ 36.87万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8749789
• 关键词: Ablation; Adaptor Signaling Protein; Address; Adipocytes; Adipose tissue; Aging; Alleles; Animals; Binding; Biochemical; Biological Process; Biology; Body Weight; Brown Fat; Cells; Complex; Control Locus; Data; Defect; Diet; Elderly; Elements; Engineering; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Genomics; Glucose Intolerance; Goals; Hepatic; Homeostasis; In Vitro; Insulin Resistance; Knock-in Mouse; Knock-out; Knockout Mice; Link; Lipids; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Molecular Genetics; Mus; Obesity; Outcome; Peroxisome Proliferator-Activated Receptors; Play; Process; Proteins; Regulation; Reporting; Role; Signal Transduction; Site; Telomere-Binding Proteins; Testing; Therapeutic; Transcription Factor AP-1; Work; adipocyte differentiation; age related; base; blood glucose regulation; bone; cofactor; forging; in vivo; insight; interest; lipid biosynthesis; mouse model; mutant; novel; protein complex; protein function; protein protein interaction; public health relevance; research study; respiratory; stem; telomere; therapeutic target; tool; transcription factor

DESCRIPTION (provided by applicant): Deciphering the extra-telomeric function of Rap1, a metabolic regulator counteracting obesity Agnel Sfeir Project Summary: The telomere-binding protein Rap1 is part of the protective protein complex that binds mammalian telomeres. It was recently found to have additional non-telomeric functions, acting as a transcriptional cofactor for different biological processes. To explore its function more thoroughly, we disrupted mouse Rap1 in vivo and reported its unanticipated role in metabolic regulation and body-weight homeostasis. Rap1 inhibition resulted in dysregulation of hepatic and adipose function, leading to glucose intolerance, insulin resistance, liver steatosis, and excess fat accumulation, resulting in eventual late-onset obesity. At the cellular level, Rap1 appears to play a pivotal role in the transcriptional cascade that controls adipocyte differentiation. Using a separation-of-function allele, we found that the metabolic function of Rap1 is independent of its recruitment to TTAGGG binding elements found at telomeres, we identify a number of possible interactors that might aid Rap1 in its metabolic function. In conclusion, our recent study, together with ongoing experiments, underscores an intriguing function for the most conserved telomere-binding protein, forging an interesting link between telomere biology and metabolic signaling. In this project, we will decipher the underlying mechanism by which Rap1 controls metabolism. Specifically, we will explore the in vivo function and mechanism of Rap1 using a set of molecular and genetic tools. We hypothesize that Rap1 regulates adipose tissue function, mainly by impinging on the transcriptional cascade that controls the remodeling of white-to-beige fat. The impact of Rap1 on metabolic gene expression is most consistent with its propensity to behave as an adaptor protein, acting within the context of a larger transcriptional complex that we plan to characterize. The extra-telomeric function of a bone fide telomere binding protein raises the intriguing possibility of telomeres behaving as a storage site for this transcriptional regulator, thereby regulating Rap1 nucleoplasmic pools available to participate in metabolism. All in all, our study is expected to provide insight into Rap1 function in metabolic control, which is pivotal for understanding dysregulation that arises when this process is mismanaged, for example in age-dependent metabolic disorders. Furthermore, our study might help identify potential therapeutic strategies for regulating excess fat accumulation and protecting against metabolic derangements.

描述（由申请人提供）：破译 Rap1 的端粒外功能，Rap1 是一种对抗肥胖的代谢调节剂 Agnel Sfeir 项目摘要：端粒结合蛋白 Rap1 是结合哺乳动物端粒的保护性蛋白复合物的一部分。最近发现它具有额外的非端粒功能，可作为转录辅助因子 不同的生物过程。为了更彻底地探索其功能，我们在体内破坏了小鼠 Rap1 并报告了其在代谢调节和体重稳态中意想不到的作用。 Rap1 抑制导致肝脏和脂肪功能失调，导致葡萄糖耐受不良、胰岛素抵抗、肝脏脂肪变性和过多的脂肪堆积，从而导致 最终导致迟发性肥胖。在细胞水平上，Rap1 似乎在控制脂肪细胞分化的转录级联中发挥着关键作用。使用功能分离等位基因，我们发现 Rap1 的代谢功能与其招募到端粒上发现的 TTAGGG 结合元件无关，我们确定了许多可能有助于 Rap1 代谢功能的相互作用因子。总之，我们最近的研究以及正在进行的实验强调了最保守的端粒结合蛋白的有趣功能，在端粒生物学和代谢信号之间建立了有趣的联系。在这个项目中，我们将破译 Rap1 控制新陈代谢的潜在机制。具体来说，我们将使用一套分子和遗传工具探索 Rap1 的体内功能和机制。我们假设 Rap1 主要通过影响控制白色脂肪重塑的转录级联来调节脂肪组织功能。 Rap1 对代谢基因表达的影响与其作为衔接蛋白的倾向最为一致，在我们计划表征的更大转录复合物的背景下发挥作用。真正的端粒结合蛋白的端粒外功能提出了端粒作为这种转录调节因子的储存位点的有趣可能性，从而调节可参与代谢的 Rap1 核质库。总而言之，我们的研究预计将深入了解 Rap1 在代谢控制中的功能，这对于理解该过程管理不当时出现的失调至关重要，例如在年龄依赖性代谢紊乱中。此外，我们的研究可能有助于确定调节多余脂肪积累和防止代谢紊乱的潜在治疗策略。