Post-transcriptional Regulation of Satellite Cell Function

卫星细胞功能的转录后调控

基本信息

批准号：
8891089
负责人：
Jason Doles
金额：
$ 9.3万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891089
关键词：
Address Adult Affect Automobile Driving Basal lamina Binding Proteins Biochemical Biochemistry Bioinformatics Biological Assay Cell membrane Cell physiology Chromatin Clinical Management Collaborations Colorado Complement Coupled Data Defect Disease Disease Progression Elements Environment Exhibits Family Family member Foundations Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Goals Growth Health Homeostasis Immunoprecipitation Injury Life Maintenance Malignant Neoplasms Mediating Mediator of activation protein Mentorship Messenger RNA 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 flexibility genetic manipulation improved in vivo insight mRNA Decay mRNA Stability malignant muscle neoplasm member multidisciplinary muscle regeneration novel post-doctoral training postnatal pre-clinical public health relevance repaired research study response sarcoma satellite cell self-renewal stem cell biology tool transcription factor tumor progression

项目摘要

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（由申请人提供）：骨骼肌的出生后生长和修复需要称为卫星细胞的成体肌肉干细胞，卫星细胞位于肌纤维膜质和基底层之间，通常保持有丝分裂静止状态，直到受到刺激激活和退出。激活期间，卫星。细胞上调MyoD，这是肌肉中的主要调节转录因子。然而，对体内卫星细胞激活的强烈控制退出和随后的MyoD表达的机制知之甚少。在这项提议中，我提出了证据，证明这些 mRNA 衰减因子之一 Tristetraprolin (TTP) 通过破坏 MyoD 的稳定性来抑制卫星细胞的激活。因此，TTP 的转录后 mRNA 调节可能在卫星细胞激活后自我更新所需的稳态维持和重新获得静止状态中发挥重要作用。 -肌肉再生期间的家族功能，2) mRNA靶向在卫星细胞激活期间介导TTP/Tis11家族功能，以及3)在肉瘤发生和进展期间该稳态网络的损坏/重新布线。研究目标与高级小鼠遗传学、RNA生物化学和生物信息学方面的实践培训相结合，并补充我之前研究癌症（研究生院）和成体干细胞信号转导（之前的博士后培训）的经验。旨在为我提供多学科概念背景和实验工具集，专门针对健康和疾病中干细胞激活的转录后机制的独立研究。科罗拉多大学博尔德分校的特殊研究环境以及密切的指导/合作。与肌肉和干细胞生物学（Olwin、Leinwand 和 Yi 博士）、mRNA 生物化学（Roy Parker 博士）和临床前小鼠肉瘤模型（David Kirsch 博士）专家的合作，将最终成功完成这些研究工作。，该提案中概述的研究和培训计划将为建立学术研究事业奠定基础，致力于了解肌肉干细胞稳态的基本机制以及这些过程在疾病中如何失调。