Apelin Signaling in Muscle Regeneration

肌肉再生中的 Apelin 信号转导

• 批准号: 10557030
• 负责人: Romain Madelaine
• 金额: $ 28.96万
• 依托单位: UNIVERSITY OF MAINE ORONO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557030
• 关键词: APLN gene; Acute; Affect; Age; Age Years; Aging; Agonist; Animals; Anti-Inflammatory Agents; Atrophic; Autoimmune Diseases; Autophagocytosis; Biogenesis; Biological; Biological Assay; Biological Models; Cell Therapy; Cells; Centers of Research Excellence; Chemicals; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cues; Data; Diabetes Mellitus; Disease; Endothelial Cells; Etiology; Fishes; Future; Gene Expression; Genes; Genetic; Goals; Health; Homeostasis; Image; Immune; Infection; Inflammation; Inflammatory; Injury; Knock-out; Long-Term Effects; Longevity; Longitudinal Studies; Macrophage; Malignant Neoplasms; Metabolic Diseases; Mitochondria; Molecular; Mus; Muscle; Muscle function; Muscle satellite cell; Muscular Atrophy; Myopathy; Natural regeneration; Obesity; Peptide Signal Sequences; Peptides; Persons; Phenotype; Population; Proliferating; Receptor Activation; Receptor Gene; Recovery; Regenerative response; Rejuvenation; Role; Series; Signal Pathway; Signal Transduction; Skeletal Muscle; Swimming; Symptoms; System; Technology; Testing; Therapeutic; Tissues; Transgenic Organisms; Zebrafish; age effect; age related; age-related muscle loss; aged; angiogenesis; anti aging; cell behavior; cell growth regulation; cell type; experimental study; extracellular; gain of function; genetic approach; genome editing; healthy aging; improved; injured; insight; intercellular communication; loss of function; mortality risk; muscle aging; muscle degeneration; muscle form; muscle regeneration; muscle strength; mutant; novel; pharmacologic; pleiotropism; prevent; receptor; regenerative; response; sarcopenia; senescence; single-cell RNA sequencing; skeletal muscle wasting; stem cell function; stem cell homeostasis; therapeutic target; tissue degeneration; transcriptomics

Abstract: Apelin Signaling Pathway In Muscle Regeneration And Rejuvenation PI: Madelaine Romain How extracellular signals and cell-to-cell communication dysregulation affect tissue homeostasis during aging are still poorly understood. The age associated muscle disease, sarcopenia, affects more than 60% of people over 80 years of age and results in mobility disorders and a significantly increased risk of mortality. Identifying dysregulated biological mechanisms involved in the etiology of sarcopenia is critical to develop therapeutic treatments to limit muscle atrophy. Recently, the expression of the apelin peptide has been shown to decline with age, correlating with an increased inflammation, senescence, and degeneration of the muscle tissue. Interestingly, treatments with the apelin peptide improve muscle regeneration and muscular function in aged animals, indicating a role in muscle regeneration and rejuvenation. However, the molecular and cellular mechanisms underlying apelin function are largely unknown, and the apelin dependent cellular crosstalk between muscle stem cells (MuSC), endothelial cells, and immune cells contributing to enhanced muscle regeneration are uncharacterized. Using the zebrafish as a model system, we will combine novel pharmacological genetic approaches to perform state of the art apelin loss and gain of function studies and use single cell RNA sequencing to identify downstream effectors of apelin that limit the impacts of aging. We propose to test the function of apelin as an anti-aging and pro-regenerative signaling peptide and decipher cell type specific functions of apelin during muscle aging and regeneration. This COBRE project includes two specific aims. During the first aim, we will use a recently discovered chemical agonist of the apelin receptors and newly generated Cre/Lox zebrafish transgenic lines to determine how chronic and genetically-induced muscle-derived apelin affects the hallmarks of muscle aging (atrophy, senescence, inflammation…). Novel CRISPR/Cas-9 zebrafish mutants will also us allow to test the function of the apelin receptor activation in MuSC, endothelial cells and macrophages to decipher the cell type-specific apelin functions during muscle aging and regeneration. Using state of the art single cell RNA-sequencing, aim 2 will reveal a set of genes regulating MuSC transition into proliferation after injury. Taking advantage of the apelin receptors mutant fish, this transcriptomic analysis should also lead to the identification of regenerative factors underlying apelin functions in MuSC-dependent regenerative response. Successful completion of these aims will define the role of the apelin signaling in multiple different cell types during muscle aging and reveal molecular and cellular therapeutic targets to alleviate or reverse age-associated sarcopenia.

翻译后摘要：Apelin信号通路在肌肉再生和返老还童 PI：Madelaine Romain 细胞外信号和细胞间通讯失调如何影响衰老过程中的组织稳态 仍然知之甚少。与年龄相关的肌肉疾病，肌肉减少症，影响超过60%的人 80岁以上的老年人，导致行动障碍和死亡风险显著增加。识别 涉及肌肉减少症病因学的失调生物学机制对于开发治疗性药物是至关重要的。 限制肌肉萎缩的治疗方法。最近，已经显示爱帕琳肽的表达下降， 随着年龄的增长，与增加的炎症、衰老和肌肉组织的退化相关。 有趣的是，用爱帕琳肽治疗改善了老年人的肌肉再生和肌肉功能。 动物，表明在肌肉再生和恢复活力的作用。然而，分子和细胞 Apelin功能的潜在机制在很大程度上是未知的，并且Apelin依赖性细胞串扰（crosslinking）是细胞内信号转导的一个重要机制。 肌肉干细胞（MuSC），内皮细胞和免疫细胞之间有助于增强肌肉 再生是不确定的。利用斑马鱼作为模型系统，我们将联合收割机与新的 药理学遗传学方法来进行最新技术水平的爱帕琳蛋白功能丧失和获得的研究和应用 单细胞RNA测序以鉴定限制衰老影响的爱帕琳的下游效应物。我们 建议测试爱帕琳作为抗衰老和促再生信号肽的功能， apelin在肌肉老化和再生过程中的类型特异性功能。COBRE项目包括两个 明确的目标。在第一个目标中，我们将使用最近发现的apelin受体的化学激动剂 和新产生的Cre/Lox斑马鱼转基因系，以确定慢性和遗传诱导 肌肉来源的爱帕琳影响肌肉老化的标志（萎缩、衰老、炎症.）。小说 CRISPR/Cas-9斑马鱼突变体也将允许我们测试apelin受体激活在斑马鱼中的功能。 MuSC、内皮细胞和巨噬细胞在肌肉生长过程中破译细胞类型特异性爱帕琳蛋白功能 老化和再生。使用最先进的单细胞RNA测序，目标2将揭示一组基因 调节损伤后MuSC向增殖的转变。利用apelin受体突变鱼， 这种转录组学分析也将导致对apelin基础的再生因子的鉴定 在MuSC依赖性再生反应中发挥作用。成功完成这些目标将确定 肌肉衰老期间多种不同细胞类型中爱帕琳信号传导的研究，揭示了分子和细胞 治疗靶点，以减轻或逆转年龄相关的肌肉减少症。