Promotion of satellite cell proliferation by cAMP signaling

cAMP 信号传导促进卫星细胞增殖

基本信息

批准号：
10363649
负责人：
Rebecca L Berdeaux
金额：
$ 37.08万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-04 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10363649
关键词：
Activator Appliances Acute Adult Aging Area Biochemical Biochemical Genetics CREB1 gene CREBBP gene Cell Nucleus Cell Proliferation ChIP-seq Complex Coupled Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein Elderly Embryo Embryonic Development G-Protein-Coupled Receptors Gene Activation Genes Genetic Genetic Transcription Genomics Goals Health In Vitro Individual Injury Knock-in Knockout Mice Ligands Maintenance Mass Spectrum Analysis Molecular Mus Muscle Muscle Fibers Muscle function Muscle satellite cell Muscular Dystrophies Myoblasts Myopathy Natural regeneration Pathway interactions Patients Pharmacology Population Post-Translational Protein Processing Proliferating Regulation Role Signal Pathway Signal Transduction Signaling Protein Skeletal Muscle Skeletal Muscle Satellite Cells Testing Transcription Coactivator age related chemical genetics designer receptors exclusively activated by designer drugs gain of function improved in vitro testing in vivo in vivo regeneration innovation insight muscle form muscle regeneration mutant new therapeutic target overexpression preservation progenitor programs promoter recruit regeneration function release factor response response to injury sarcopenia satellite cell skeletal disorder skeletal muscle wasting stem cell population stem cell proliferation stem cells tool transcription factor transcriptome sequencing transcriptomics

项目摘要

SUMMARY Skeletal muscle regeneration requires activation and proliferation of a resident population of stem cells known as satellite cells. Satellite cells are not only required for muscle regeneration after injury but are also thought to contribute to ongoing maintenance of muscle mass. Unfortunately, the number and activity of these progenitors declines with aging and muscular dystrophy. Therefore, pharmacologic strategies to promote expansion of myogenic satellite cells could potentially be used to improve muscle regeneration and preserve muscle function in individuals with muscle disease or individuals of advanced age. Signaling through the cAMP pathway stimulates myogenic progenitor cell proliferation during embryonic development and is sufficient to stimulate proliferation of these cells in vitro. This pathway is also activated during regeneration in adult mice. However, it is unknown whether cAMP signaling in myogenic progenitor cells in response to injury is sufficient to enhance proliferation in vivo. We previously showed that the cAMP-responsive transcription factor CREB is activated in areas of proliferation after acute muscle injury in mice and that mice expressing an activated mutant of CREB have enhanced myoblast proliferation after injury. This project employs biochemical and chemical-genetic tools to determine whether chemical-genetic elevation and genetic regulation of cAMP signaling specifically in satellite cells alters proliferation and muscle regeneration in vivo through regulation of CREB/CRTC transcriptional complexes. We will interrogate the regulation and function of cAMP-regulated CREB co-activators (CRTCs) in satellite cell proliferation and use unbiased transcriptomic approaches to identify CREB/CRTC target genes that contribute to the cAMP-driven proliferative response. We will undertake mechanistic studies to characterize molecular regulation of CRTCs and the mechanism of CRTC recruitment to cAMP-regulated genes in proliferating satellite cells. Results of this project will yield insights into fundamental mechanisms that drive satellite cell proliferation and expansion. The long-term goal is to identify new pharmacologic targets to improve muscle regeneration and function in patients with muscle disease and age-related sarcopenia.

概括骨骼肌再生需要激活和增殖已知的干细胞种群作为卫星细胞。卫星细胞不仅需要受伤后的肌肉再生，而且还被认为是有助于持续维持肌肉质量。不幸的是，这些祖细胞的数量和活动衰老和肌肉营养不良的下降。因此，促进扩展的药理策略肌源性卫星细胞可能可用于改善肌肉再生并保留肌肉功能在患有肌肉疾病或高年龄的个体中。通过营地通道发出信号在胚胎发育过程中刺激肌源性祖细胞增殖，足以刺激这些细胞在体外的增殖。在成年小鼠再生过程中，该途径也被激活。但是，它尚不清楚肌源性祖细胞中的cAMP信号是否足以增强体内增殖。我们先前证明了营地响应转录因子CREB被激活小鼠急性肌肉损伤后增殖的区域，而小鼠表达了激活的CREB突变体受伤后已经增强了肌细胞增殖。该项目员工的生化和化学遗传工具确定卫星中cAMP信号的化学遗传升高和遗传调节是否特殊细胞通过调节CREB/CRTC转录来改变体内的增殖和肌肉再生复合物。我们将询问cAMP调节的CREB共激活因子（CRTC）的调节和功能卫星细胞增殖并使用公正的转录组方法来识别CREB/CRTC靶基因有助于营地驱动的增殖物响应。我们将进行机械研究以表征 CRTC的分子调节以及CRTC募集到cAMP调节基因的机制增殖的卫星细胞。该项目的结果将产生对驱动基本机制的见解卫星细胞增殖和扩张。长期目标是确定新的药理目标以改进肌肉疾病和与年龄相关的肌肉减少症患者的肌肉再生和功能。