Proliferation competence of skeletal muscle stem cells

骨骼肌干细胞的增殖能力

• 批准号: 10152518
• 负责人: CHEN-MING FAN
• 金额: $ 34.47万
• 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/10152518
• 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.

项目总结 骨骼肌可以通过使用驻留的肌肉干细胞在一生中再生。肌肉干细胞 通常是静止的。一旦受到损伤刺激，它们就会增殖，形成新的肌肉，即再生。 在再生过程中，肌肉干细胞也会自我更新，并回到静止状态，以便培养 未来几轮的再生。在老化过程中，在一定的实验条件下，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。然而，在这种情况下， 肌肉干细胞不会回到静止状态并丢失。肌肉干细胞的丧失对人体产生负面影响 肌肉再生。驱动肌肉干细胞在不损伤的情况下增殖的原因与 静止的肌肉干细胞内的“增殖能力”。我们感兴趣的是分子是否 在静止状态下这种“增殖能力”的机制与损伤有相似之处，也有区别。 刺激诱导的增殖计划。 我们以前已经证明了环-AMP反应元件结合蛋白(CREB)家族(CREB， 转录激活子调控小鼠骨骼肌造血祖细胞的命运 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家族需要激活静止期肌肉中的一组基因 干细胞，但不需要维持它们的静止状态。然而，CREB家族的肌肉干细胞 损伤刺激后被抑制的细胞不能增殖或更新。我们鉴定出一种叫做Mpp7的蛋白质是一种 CREB家族下游的候选介体，驱动肌肉干细胞的增殖和更新。 我们认为这种蛋白质和它的一个相关蛋白质复合体共同构成核心。 静止期和损伤诱导的增殖能力的机制。 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)我们将从基因上确定Mpp7是否确实对肌肉干细胞的增殖和 更新；2)我们将调查Mpp7相关蛋白复合体是否对增殖和 利用siRNA筛选和遗传学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相关蛋白复合体，并探索其在机械传感中的潜在参与。