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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：
10583531
负责人：
Rebecca L Berdeaux
金额：
$ 37.18万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583531
关键词：
Activator Appliances Acute Adult Aging Area Biochemical Biochemical Genetics CREB1 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 Population Post-Translational Protein Processing Proliferating Regulation Role Signal Induction Signal Pathway Signal Transduction Skeletal Muscle Skeletal Muscle Satellite Cells Stimulation of Cell Proliferation 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 pharmacologic preservation progenitor programs promoter recruit 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.

总结骨骼肌再生需要已知的干细胞常驻群体的激活和增殖。作为卫星细胞。卫星细胞不仅是肌肉损伤后再生所必需的，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性，随着年龄的增长和肌肉营养不良而下降。因此，促进扩张的药理学策略，肌源性卫星细胞可用于促进肌肉再生和保护肌肉功能在肌肉疾病的个体或高龄个体中。通过cAMP途径的信号传导在胚胎发育过程中刺激肌原祖细胞增殖，这种途径在成年小鼠的再生过程中也被激活。然而，尚不清楚肌源性祖细胞对损伤的反应中的cAMP信号传导是否足以增强我们以前的研究表明，cAMP-β反应性转录因子CREB被激活，小鼠急性肌肉损伤后的增殖区域以及表达CREB激活突变体的小鼠增强了损伤后成肌细胞的增殖。该项目采用了生物化学和化学遗传学工具以确定是否在卫星中特异性地化学诱导遗传升高和cAMP信号传导的遗传调节，细胞通过调节CREB/CRTC转录改变体内增殖和肌肉再生我们将探讨cAMP-β调节的CREB共激活物（CRTCs）在细胞内的调节和功能。卫星细胞增殖，并使用无偏转录组学方法来鉴定CREB/CRTC靶基因，有助于cAMP-β驱动的增殖反应。我们将进行机制研究， CRTC的分子调控和CRTC募集到cAMP-β调节基因的机制，增殖的卫星细胞。该项目的结果将产生深入了解的基本机制，卫星细胞增殖和扩增。长期目标是确定新的药理学靶点，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。