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: 9298637
• 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/9298637
• 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; Data; Defect; Elderly; Elements; Engineering; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genomics; Glucose Intolerance; Goals; Hepatic; High Fat Diet; Homeostasis; In Vitro; Insulin Resistance; Knock-in; 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; Recruitment Activity; Regulation; Reporting; Role; SIRT1 gene; Signal Transduction; Site; Telomere-Binding Proteins; Testing; Therapeutic; Transcription Factor AP-1; Treatment Efficacy; Work; activator 1 protein; adipocyte differentiation; age related; blood glucose regulation; bone; cofactor; experimental study; forging; in vivo; insight; lipid biosynthesis; mouse model; mutant; novel; protein complex; protein function; protein protein interaction; public health relevance; respiratory; stem; telomere; telomere loss; 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(申请人提供)：破译Rap1的端粒外功能，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质复合体的一部分。最近发现它还有额外的非端粒功能，作为一种转录辅助因子 不同的生物过程。为了更深入地探索它的功能，我们在体内干扰了小鼠RAP1，并报告了它在代谢调节和体重动态平衡中出人意料的作用。抑制RAP1导致肝脏和脂肪功能失调，导致糖耐量异常、胰岛素抵抗、肝脏脂肪变性和过量脂肪堆积，从而导致 最终导致迟发性肥胖症。在细胞水平上，Rap1似乎在控制脂肪细胞分化的转录级联中起着关键作用。利用功能分离等位基因，我们发现Rap1的代谢功能不依赖于它对端粒上发现的TTAGGG结合元件的募集，我们发现了一些可能的相互作用因素，可能有助于Rap1的代谢功能。总之，我们最近的研究，加上正在进行的实验，强调了最保守的端粒结合蛋白的一个有趣的功能，在端粒生物学和代谢信号之间建立了一个有趣的联系。在这个项目中，我们将破译Rap1控制新陈代谢的潜在机制。具体地说，我们将使用一系列分子和遗传工具来探索Rap1的体内功能和机制。我们假设RAP1调节脂肪组织的功能，主要是通过影响控制从白色到米色脂肪重塑的转录级联。Rap1对代谢基因表达的影响与其作为适配蛋白的倾向最一致，在我们计划表征的更大的转录复合体的背景下发挥作用。骨性端粒结合蛋白的端粒外功能增加了端粒作为这种转录调节因子的存储位置的有趣的可能性，从而调节可用于参与新陈代谢的Rap1核质库。总而言之，我们的研究有望提供对Rap1在代谢控制中的作用的洞察，这对于理解这一过程管理不善时出现的调节失调至关重要，例如在年龄相关性代谢障碍中。此外，我们的研究可能有助于确定潜在的治疗策略，以调节过量脂肪积累和防止代谢紊乱。