Post-transcriptional Regulation of Satellite Cell Function

卫星细胞功能的转录后调控

• 批准号: 9304882
• 负责人: Jason Doles
• 金额: $ 30.7万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304882
• 关键词: Address; Adult; Affect; Automobile Driving; Basal lamina; Binding Proteins; Biochemical; Biochemistry; Bioinformatics; Biological Assay; Cell membrane; Cell physiology; Cellular biology; Chromatin; Clinical Management; Collaborations; Colorado; Complement; Coupled; Data; Defect; Disease; Disease Progression; Elements; Environment; Exhibits; Family; Family member; Foundations; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Goals; Growth; Health; Homeostasis; Immunoprecipitation; Injury; Life; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentorship; Messenger RNA; Mitotic; Modeling; Mus; Muscle; Muscle satellite cell; Myogenic Regulatory Factors; Myopathy; Natural regeneration; Phase; Play; Population; Post-Transcriptional Regulation; Process; Proteins; RNA Biochemistry; RNA Interference; RNA-Binding Proteins; Regulation; Research; Research Training; Role; Schools; Signal Transduction; Skeletal Muscle; Stem cells; TIS11 protein; Technology; Testing; Tissues; Training; Transcript; Transcription Coactivator; Tumor-Derived; Universities; Validation; Work; adult stem cell; base; career; cell type; crosslink; design; experience; experimental study; flexibility; genetic manipulation; improved; in vivo; insight; knock-down; mRNA Decay; mRNA Stability; malignant muscle neoplasm; member; mouse model; multidisciplinary; muscle regeneration; novel; post-doctoral training; postnatal; pre-clinical; public health relevance; repaired; response; sarcoma; satellite cell; self-renewal; tool; transcription factor; transcriptome; tumor progression

 DESCRIPTION (provided by applicant): Postnatal growth and repair of skeletal muscle requires adult muscle stem cells called satellite cells. Located between the myofiber plasma membrane and the basal lamina, satellite cells are generally maintained as a mitotically quiescent population until stimulated to activate and exit quiescence. During activation, satellite cells upregulate MyoD, a master regulatory transcription factor in muscle. However, the mechanisms governing exit from quiescence and subsequent MyoD expression are poorly understood. Gene expression profiling of in vivo satellite cell activation revealed significant depletion of transcripts encoding proteins involved in mRNA decay, strongly implicating post-transcriptional mRNA regulation in satellite cell activation. In this proposal, I present evidence that one of these mRNA decay factors, Tristetraprolin (TTP), suppresses satellite cell activation by destabilizing MyoD mRNA. Thus, post-transcriptional mRNA regulation by TTP may play an important role in the steady-state maintenance and re-acquisition of satellite cell quiescence required for satellite cell self-renewal following activation. This proposal will address: 1) TTP/Tis11-family function during muscle regeneration, 2) mRNA targets mediating TTP/Tis11-family function during satellite cell activation, and 3) corruption/rewiring of this homeostatic network during sarcoma initiation and progression. These research aims are coupled with hands-on training components in advanced mouse genetics, RNA biochemistry, and bioinformatics, and complement my previous experiences studying cancer (graduate school) and adult stem cell signaling (prior postdoctoral training). The opportunities outlined in this proposal are designed to provide me with a multidisciplinary conceptual background and experimental toolset tailored towards independent study of post-transcriptional mechanisms of stem cell activation in health and disease. An exceptional research environment at the University of Colorado-Boulder as well as close mentorship by/collaboration with experts in muscle and stem cell biology (Drs. Olwin, Leinwand and Yi), mRNA biochemistry (Dr. Roy Parker) and pre-clinical mouse sarcoma models (Dr. David Kirsch), will enable successful completion of these research endeavors. Ultimately, the research and training plan outlined in this proposal will lay a foundation for the establishment of an academic research career dedicated to understanding fundamental mechanisms of muscle stem cell homeostasis and how these processes are deregulated in disease.

 描述（由适用提供）：骨骼肌产后生长和修复需要成年肌肉干细胞称为卫星细胞。卫星细胞位于肌纤维质膜和碱性层之间，通常将卫星细胞保持为有丝分裂的静态种群，直到被刺激以激活和退出静止为止。激活期间，卫星 细胞上调肌肉中的主要调节转录因子Myod。但是，对静止和随后的MYOD表达的退出的机制知之甚少。体内卫星细胞激活的基因表达分析表明，编码与mRNA衰变有关的蛋白质的转录本的显着部署，强烈暗示卫星细胞激活中的转录后mRNA调节。在此提案中，我提供了证据表明，这些mRNA衰减因子之一三翼酸（TTP）通过破坏MYOD mRNA的稳定来抑制卫星细胞的激活。这是，TTP的转录后mRNA调节可能在激活后卫星细胞自我更新所需的卫星细胞静脉静止和重新获得卫星细胞静止中起重要作用。该提案将解决：1）肌肉再生期间TTP/TIS11家庭功能，2）mRNA靶标在卫星细胞激活过程中介导TTP/TIS11-家庭功能，以及3）在肉瘤开始和进展过程中，该体内稳态网络的损坏/转移。这些研究的目的与高级小鼠遗传学，RNA生物化学和生物信息学的动手训练组件相结合，并补充了我以前研究癌症（研究生院）和成人干细胞信号（事先博士后培训）的经验。该提案中概述的机会旨在为我提供多学科的概念背景和实验性工具集，用于独立研究健康和疾病中干细胞激活后的转录后机制。科罗拉多大学 - 博尔德大学的卓越研究环境以及与肌肉和干细胞生物学专家（Olwin，Leinwand和Yi博士），MRNA BioChemistry（Roy Parker博士）和临床前鼠标肉瘤模型（David Kirsch博士）的亲密心态（Roy Parker博士），将成功完成这些研究。最终，该提案中概述的研究和培训计划将为建立致力于理解肌肉干细胞体内稳态的基本机制以及这些过程如何在疾病中放松管制的学术研究生涯奠定基础。