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Cell-cycle commitment in muscle regeneration

肌肉再生中的细胞周期承诺

基本信息

批准号：
10237173
负责人：
Mingyu Chung
金额：
$ 6.89万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-16 至 2023-07-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237173
关键词：
Address Aging Automobile Driving Biochemical Biological Assay Biology CDK4 gene Cell Cycle Cell Cycle Completion Cell Cycle Progression Cell Proliferation Cell Separation Cell physiology Cells Cyclin D1 Cyclin-Dependent Kinases Cyclins Data Defect Degenerative Disorder Dependence Epithelial Cells Excision Exhibits Fellowship Fibroblasts Fluorescent in Situ Hybridization G0 Phase G1 Phase Gene Expression Generations Genes Genetic Transcription Goals Growth Factor Harvest Histology Image Image Analysis Immunofluorescence Immunologic In Vitro Injections Injury Knockout Mice Knowledge Lead Maintenance Malignant Neoplasms Maps Mediating Methodology Methods Mitogens Modeling Molecular Muscle Muscle satellite cell Pathology Process RNA Research Role Science Scientist Signal Transduction Skeletal Muscle Small Interfering RNA System Technology Testing Therapeutic Time Tissues Western Blotting Work adult stem cell base career conditional knockout experimental study extracellular in vivo in vivo evaluation insight mRNA Expression muscle regeneration protein expression regeneration following injury regenerative response satellite cell skills stem cell proliferation stem cells therapeutic target time use tissue regeneration transcriptome transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Mammalian tissues exhibit remarkable regenerative activity following injury, and defects in this process are associated with aging and degenerative diseases. Skeletal muscle regeneration requires a sustained proliferative response from muscle stem cells called satellite cells (SCs), yet it is unknown how this is achieved. Cellular proliferation is controlled by extracellular growth factors, or mitogens. The process of cellular proliferation, referred to as the cell cycle, involves cells exiting a non-proliferative G0 state and initiating the cell cycle in G1. At some point in G1, cells effectively escape the requirement for mitogens and commit to mitogen- independent completion of the cell cycle, but subsequent rounds of proliferation each require mitogen signaling during or just before G1. Insights into cell-cycle commitment mechanisms are primarily derived from in vitro studies of fibroblasts and immortalized epithelial cells, but it is unclear how relevant such systems are to the process of SC activation, where SCs exhibit a prolonged first G0/G1 phase, followed by multiple rounds of proliferation. Our preliminary work indicates that a mechanism of bistability, where a process remains indefinitely engaged despite the removal of mitogens, underlies cell-cycle commitment in the G0/G1 phase of SCs. The central hypothesis of this proposal is that a bistable G0/G1 mechanism underlies multiple rounds of mitogen-independent SC proliferation and effective muscle regeneration. The proposed work addresses the following specific aims: 1. Identify the mechanism of SC cell-cycle commitment through prolonged and multiple G0/G1 phases. 2. Establish mitogen signaling dynamics during muscle regeneration. 3. Determine the role of SC G0/G1 cell-cycle commitment during muscle regeneration. The mechanism of G0/G1 cell-cycle commitment will be identified using FACS-based SC isolation and ex vivo assays, including time-lapse imaging, immunofluorescence, and automated cell tracking and image analysis. In vivo mitogen signaling dynamics will be investigated using a muscle injury model and harvesting muscles for biochemical and transcriptomic analysis of growth factor availability and SC mitogen signaling. The functional role of SC G0/G1 cell-cycle commitment mechanisms in muscle regeneration will be tested using SC-specific conditional knockout mice and rescue by ectopic introduction of mitogens. Stanford is a leader in stem cell and regenerative sciences and will provide me with the technologies and collaborative network to develop into an independent research scientist. This research will uncover the fundamental relationship between mitogens and stem cell proliferation during muscle regeneration and may lead to therapeutic strategies for treating regenerative defects in aging and degenerative diseases.

项目总结/文摘