Proliferation competence of skeletal muscle stem cells

骨骼肌干细胞的增殖能力

• 批准号: 9752475
• 负责人: CHEN-MING FAN
• 金额: $ 35.54万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752475
• 关键词: AMOT gene; Adherens Junction; Adult; Aging; Apical; Binding Proteins; Biochemical; Cell Cycle; Cell Line; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Common Core; Competence; Complex; Cyclic AMP-Responsive DNA-Binding Protein; Data; Dominant-Negative Mutation; Embryo; Epithelial Cells; Fostering; Future; Genes; Genetic Transcription; Genetic study; In Vitro; Injury; Knock-out; Lateral; Length; LoxP-flanked allele; Maps; Mediating; Mediator of activation protein; Membrane; Membrane Proteins; Molecular; Mus; Muscle; Muscle satellite cell; Muscular Atrophy; Myoblasts; Natural regeneration; Nuclear; Pathway interactions; Phenotype; Play; Process; Proliferating; Protein Family; Proteins; Regulation; Research; Role; Skeletal Muscle; Small Interfering RNA; Stem cells; Stimulus; Testing; Tight Junctions; Transcription Coactivator; Work; activating transcription factor; activating transcription factor 1; in vivo; interest; mechanotransduction; muscle regeneration; mutant; prevent; progenitor; programs; protein complex; protein function; satellite cell; self-renewal; skeletal

PROJECT SUMMARY Skeletal muscles can regenerate throughout lifetime by using resident muscle stem cells. Muscle stem cells are normally quiescent. Upon injury stimuli, they can proliferate to make new muscles, i.e. regeneration. During regeneration, muscle stem cells also renew themselves and return to quiescence so they can foster future rounds of regeneration. During the aging process and under certain experimental conditions, muscle stem cells can also break quiescence and proliferate without injury stimuli. However, under these conditions muscle stem cells do not return to quiescence and become lost. Loss of muscle stem cells negatively impacts muscle regeneration. What drives muscle stem cells to proliferate without injury pertains to a cellular state of `proliferation competence' within quiescent muscle stem cells. We are interested in whether the molecular machinery for this `proliferation competence' during quiescence shares similarity with or differs from injury stimuli-induced proliferation program. We have previously shown that the cyclic-AMP-responsive-element binding protein (CREB) family (CREB, CREM, and ATF1) of transcriptional activators regulates skeletal myogenic progenitor fate in the mouse embryo. To test whether the CREB family plays a role in adult muscle regeneration, we inhibited the CREB family in muscle stem cells. We found that CREB family is need to activate a set of genes in quiescent muscle stem cells, but not needed to maintain their quiescence. However, muscle stem cells with CREB family inhibited cannot proliferate or renew following injury stimuli. We identified a protein called Mpp7 as a candidate mediator acting downstream of CREB family to drive muscle stem cell proliferation and renewal. We propose that this protein, together with one of its associated protein complexes, constitute common core machinery for proliferation competence during quiescence and injury-induced proliferation. Our proposed research is aimed to determine whether and how Mpp7 instructs muscle stem cell function: 1) We will determine genetically whether Mpp7 is indeed critical for muscle stem cell proliferation and renewal; 2) We will investigate whether a Mpp7-associated protein complex is responsible for proliferation and renewal of muscle stem cells using siRNA screens and genetic studies; 3) We will further determine the biochemical and molecular mechanisms underlying proliferation and renewal of muscle stem cells driven by the Mpp7-associated protein complex, and explore its potential involvement in mechano-sensing.

项目摘要 骨骼肌可以通过使用常驻肌肉干细胞在整个生命周期中再生。肌肉干细胞 通常是静止的。损伤刺激后，它们可以扩散以产生新的肌肉，即再生。 在再生期间，肌肉干细胞也会更新并恢复静止，以便它们可以促进 未来再生一轮。在衰老过程和某些实验条件下，肌肉 干细胞也可以在没有损伤刺激的情况下打破静止和增殖。但是，在这些条件下 肌肉干细胞不会恢复静止并丢失。肌肉干细胞的丧失会对 肌肉再生。是什么驱动肌肉干细胞在没有损伤的情况下增殖的原因与细胞状态有关 静态肌肉干细胞中的“增殖能力”。我们对分子是否感兴趣 静止期间这种“增殖能力”的机械与受伤有相似性或不同 刺激引起的增殖计划。 我们先前已经表明，环状响应 - 元素结合蛋白（CREB）家族（CREB， 转录激活剂的CREM和ATF1）调节小鼠中骨骼肌生祖细胞的命运 胚胎。为了测试CREB家族是否在成人肌肉再生中起作用，我们抑制了Creb 肌肉干细胞中的家庭。我们发现Creb家族需要在静止的肌肉中激活一组基因 干细胞，但不需要保持其静止。但是，具有CREB家族的肌肉干细胞 受伤刺激后抑制不能增殖或更新。我们确定了一种称为MPP7的蛋白 Creb家族下游的候选介质以驱动肌肉干细胞增殖和更新​​。 我们建议该蛋白质及其相关蛋白质复合物构成共同核心 在静止和损伤引起的增殖过程中增殖能力的机械。 我们提出的研究旨在确定MPP7是否以及如何指导肌肉干细胞功能： 1）我们将从遗传上确定MPP7是否确实对于肌肉干细胞增殖至关重要 更新； 2）我们将调查与MPP7相关的蛋白质复合物是否负责增殖和 使用siRNA筛选和遗传研究更新肌肉干细胞； 3）我们将进一步确定 生化和分子机制的增殖和更新​​的肌肉干细胞的更新 与MPP7相关的蛋白质复合物，并探索其潜在参与机械感应。