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再生。肌肉干细胞 通常是静止的。在损伤刺激下，它们可以增殖以产生新的肌肉，即再生。 在再生过程中，肌肉干细胞也会自我更新并恢复静止状态，以便它们能够培养 未来几轮的再生。在衰老过程中，在一定的实验条件下， 干细胞还可以在没有损伤刺激的情况下打破静止并增殖。然而，在这种情况下， 肌肉干细胞不会恢复静止状态而丢失。肌肉干细胞的丧失对 肌肉再生是什么驱使肌肉干细胞在没有损伤的情况下增殖，这与肌肉干细胞的细胞状态有关。 静止肌肉干细胞内的“增殖能力”。我们感兴趣的是， 静止期这种“扩散能力”的机制与损害有相似之处，也有不同之处 刺激诱导的增殖计划。 我们先前已经表明，环AMP反应元件结合蛋白（CREB）家族（CREB， CREM和ATF 1）调节小鼠骨骼肌祖细胞命运 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家族的表达。 肌肉干细胞我们发现CREB家族是激活静止期肌肉中一组基因所必需的 干细胞，但不需要维持它们的静止。然而，具有CREB家族的肌肉干细胞 受抑制的细胞在受到损伤刺激后不能增殖或更新。我们发现了一种叫做Mpp 7的蛋白质， 在CREB家族下游起作用的候选介质，以驱动肌肉干细胞增殖和更新。 我们认为，这种蛋白质，连同其相关的蛋白质复合物之一，构成共同的核心 在静止和损伤诱导的增殖过程中的增殖能力。 我们提出的研究旨在确定Mpp 7是否以及如何指导肌肉干细胞功能： 1)我们将从遗传学上确定Mpp 7是否确实对肌肉干细胞增殖至关重要， 2）我们将研究Mpp 7相关蛋白复合物是否负责增殖， 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 肌肉干细胞增殖和更新的生化和分子机制 Mpp 7相关蛋白复合物，并探讨其在机械传感的潜在参与。