Proliferation competence of skeletal muscle stem cells

骨骼肌干细胞的增殖能力

• 批准号: 10401275
• 负责人: CHEN-MING FAN
• 金额: $ 35.18万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401275
• 关键词: AMOT gene; Adherens Junction; Adult; Aging; Apical; Binding Proteins; Biochemical; Cell Cycle; Cell Line; Cell Nucleus; Cell Proliferation; 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; 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; Stimulus; Testing; Tight Junctions; Transcription Coactivator; Work; activating transcription factor; activating transcription factor 1; conditional knockout; in vivo; interest; mechanotransduction; muscle regeneration; mutant; prevent; progenitor; programs; protein complex; protein function; satellite cell; self-renewal; skeletal; stem cell function; stem cell proliferation; stem cells

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.

项目概要 骨骼肌可以通过使用常驻肌肉干细胞在一生中再生。肌肉干细胞 通常是静止的。在受到伤害刺激时，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，以便它们可以培育 未来几轮的再生。在衰老过程中，在一定的实验条件下，肌肉 干细胞还可以在不受损伤刺激的情况下打破静止并增殖。然而在这些条件下 肌肉干细胞不会恢复静止并丢失。肌肉干细胞的损失会产生负面影响 肌肉再生。驱动肌肉干细胞在不受损伤的情况下增殖的因素与以下细胞状态有关： 静止肌肉干细胞内的“增殖能力”。我们感兴趣的是分子是否 静止期间这种“增殖能力”的机制与损伤有相似之处或不同之处 刺激诱导的增殖程序。 我们之前已经证明环AMP反应元件结合蛋白（CREB）家族（CREB， 转录激活因子的 CREM 和 ATF1）调节小鼠骨骼肌原祖细胞的命运 胚胎。为了测试 CREB ​​家族是否在成人肌肉再生中发挥作用，我们抑制了 CREB 肌肉干细胞家族。我们发现CREB家族需要激活静止肌肉中的一组基因 干细胞，但不需要维持其静止状态。然而，具有CREB家族的肌肉干细胞 受到抑制后，损伤刺激后不能增殖或更新。我们鉴定出一种名为 Mpp7 的蛋白质 候选介质作用于 CREB ​​家族下游，驱动肌肉干细胞增殖和更新​​。 我们认为这种蛋白质与其相关的蛋白质复合物之一构成了共同的核心 静止和损伤诱导的增殖期间增殖能力的机制。 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) 我们将从基因角度确定 Mpp7 是否确实对肌肉干细胞增殖至关重要，并且 更新； 2）我们将研究Mpp7相关蛋白复合物是否负责增殖和 使用 siRNA 筛选和基因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 Mpp7 相关蛋白复合物，并探索其在机械传感中的潜在参与。