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Quiescence of Muscle Stem Cells During Growth and Repair

肌肉干细胞在生长和修复过程中的静止

基本信息

批准号：
9043803
负责人：
Andrew S Brack
金额：
$ 35.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9043803
关键词：
Adult Aging Applications Grants Atrophic Attention Biological Assay Biology Cell Aging Cell Count Cell Cycle Cell division Cell physiology Cell surface Cells Complement Data Development Disease Embryonic Development Ensure Excision Functional disorder Genetic Growth Growth Inhibitors Heterogeneity Homeostasis In Vitro Kinetics Label Laboratories Life Long-Term Effects Maintenance Monitor Mus Muscle Muscle Fibers Muscle satellite cell Muscular Atrophy Muscular Dystrophies Myopathy Neonatal Output Phenotype Population Proliferating Property Recording of previous events Regulation Reporter Role Signal Transduction Skeletal Muscle Specific qualifier value Staging Stem cells Techniques Testing Time Tissues To specify Transgenic Organisms Transplantation adult stem cell aged base cell age improved in vitro Assay in vivo inhibitor/antagonist intercellular communication muscle aging muscle regeneration myogenesis overexpression postnatal regenerative repaired sarcopenia satellite cell self-renewal sensor stem cell niche

项目摘要

DESCRIPTION (provided by applicant): Adult stem cells are capable of self renewal and differentiation. Although they possess self-renewal properties, this potential is not limitless. This begs the following question: how are stem cells maintained throughout life? The answer lies in the reversible state of quiescence. Adult stem cells are predominantly in a quiescent state interspersed with rare traverses into the cell cycle unlike their downstream descendents that spend more time in cycle. Using cell labeling techniques to monitor cell division history, stem cells that divide less frequently are enriched for self-renewal potential. In muscular dystrophies, muscle stem cells (satellite cells, SCs) undergo continuous bouts of proliferation, which leads to a depletion of the stem cell pool over time. In aged muscle the SC pool is diminished and displays impaired renewal and differentiation. Therefore understanding how 'proliferation-restricted' stem cells may hold the key to optimizing stem cell function during aging and disease. In this grant proposal we will interrogate 1) the functional heterogeneity between slow and faster dividing SCs. 2) How the slow dividing SC population is specified and maintained throughout life through Spry, an inhibitor of growth factor signaling. 3) The consequences of losing slow dividing subset of SCs SC function and muscle homeostasis during aging. Slow dividing SCs will be identified in vivo based on label retaining character (LRC) using a transgenic H2B-GFP approach; cells that undergo fewer divisions retain more label. Satellite cells will be characterized for LRC and non-LRC; both subpopulations will be tested for their functional differences based on in vivo and in vitro assays. We have generated preliminary data that demonstrates Spry1 expression is enriched in LRCs and genetic disruption of Spry1 leads to a loss of LRC in growing muscle and an accelerated decline in the number of SCs during aging. We will extend these studies to delete and overexpress Spry1 specifically in SCs in a temporally inducible manner. We will disrupt Spry1 to alter LRC establishment and maintenance and study the effects on SC function and muscle phenotype. The specific aims of this proposal are: 1) To study the slow division dynamics of satellite cells during developmental and postnatal myogenesis, 2) to identify whether Spry1 is required and sufficient to regulate LRC SCs, and 3) to understand the consequences of losing SC LRC throughout life.

描述(申请人提供)：成体干细胞具有自我更新和分化的能力。虽然它们拥有自我更新的特性，但这种潜力并不是无限的。这就引出了以下问题：干细胞是如何在一生中维持的？答案在于可逆的静止状态。成体干细胞主要处于静止状态，其间穿插着罕见的进入细胞周期的过程，不同于它们的下游后代在周期中花费更多的时间。使用细胞标记技术监测细胞分裂历史，分裂频率较低的干细胞得到丰富的自我更新潜力。在肌营养不良症中，肌肉干细胞(卫星细胞，SCs)经历持续的增殖，这会导致干细胞库随着时间的推移而耗尽。在衰老的肌肉中，SC池减少，更新和分化受损。因此，了解“增殖受限”干细胞是如何在衰老和疾病期间优化干细胞功能的关键。在这份拨款提案中，我们将询问1)慢速和快分频SC之间的功能异质性。2)如何通过生长因子信号的抑制剂Spry来指定和维持缓慢分裂的SC种群。3)衰老过程中失去SCs-SC功能的慢分裂亚群和肌肉内环境平衡的后果。缓慢分裂的干细胞将在体内根据标记保留特征(LRC)使用转基因的H2B-GFP方法进行鉴定；经历较少分裂的细胞保留更多的标记。卫星细胞将被表征为LRC和非LRC；这两个亚群将基于体内和体外测试来测试它们的功能差异。我们已经产生了初步的数据，证明Spry1在LRC中的表达丰富，并且Spry1的基因破坏导致生长肌肉中LRC的丢失和衰老过程中SCs数量的加速下降。我们将扩大这些研究的范围，以在时间上诱导的方式在干细胞中特异性地删除和过度表达Spry1。我们将干扰Spry1以改变LRC的建立和维持，并研究其对SC功能和肌肉表型的影响。这一建议的具体目的是：1)研究发育和出生后肌肉发生过程中卫星细胞的缓慢分裂动力学；2)确定Spry1是否是调节LRC SCs所必需的和足够的；3)了解Sc LRC在一生中丢失的后果。