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.

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.