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（由申请人提供）：解密RAP1的tellomeric函数，一种代谢调节剂应对肥胖的Agnel Sfeir Sfeir项目摘要：端粒结合蛋白RAP1是结合哺乳动物端粒的保护蛋白配合物的一部分。最近发现它具有额外的非质体功能，充当转录辅助因子 不同的生物过程。为了更彻底地探索其功能，我们破坏了体内小鼠RAP1，并报告了其在代谢调节和体重稳态中的意外作用。 RAP1抑制作用导致肝和脂肪功能失调，导致葡萄糖不耐症，胰岛素抵抗，肝脂肪变性和多余的脂肪积累，导致 在最终发作的肥胖症中。在细胞水平上，RAP1似乎在控制脂肪细胞分化的转录级联反应中起关键作用。使用功能分离等位基因，我们发现RAP1的代谢功能与端粒上的Ttaggg结合元素的募集无关，我们确定了许多可能有助于RAP1的可能相互作用的人。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传导之间建立了有趣的联系。在这个项目中，我们将破译RAP1控制代谢的基本机制。具体而言，我们将使用一组分子和遗传工具探索RAP1的体内功能和机制。我们假设RAP1主要是通过控制着米脂脂肪重塑的转录级联反应来调节脂肪组织功能。 Rap1对代谢基因表达的影响与其作为适配器蛋白的行为倾向最一致，该蛋白质在我们计划表征的较大的转录复合物的背景下作用。骨端粒结合蛋白的theperomeric功能增加了端粒作为该转录调节剂的存储位点的有趣可能性，从而调节可用于参与代谢的RAP1核型池。总而言之，我们的研究应在代谢控制中提供对RAP1功能的见解，这对于理解该过程不雄辩的失调的关键是关键的，例如，在年龄依赖性代谢性疾病中。此外，我们的研究可能有助于确定调节过量脂肪积累并保护代谢危险的潜在治疗策略。