Apelin Signaling in Muscle Regeneration

肌肉再生中的 Apelin 信号转导

基本信息

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
项目类别：
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

项目摘要

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.

摘要：Apelin 信号通路在肌肉再生和恢复中的作用 PI：玛德琳·罗曼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人们对与年龄相关的肌肉疾病——肌肉减少症——的了解仍然知之甚少，它影响着超过 60% 的人。 80 岁以上，导致行动障碍，死亡风险显着增加。肌肉减少症病因学失调的生物学机制对于开发治疗方法至关重要限制肌肉萎缩的治疗最近已显示 apelin 肽的表达下降。随着年龄的增长，与肌肉组织炎症、衰老和退化的增加相关。治疗、apelin 肽治疗可改善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方面有作用，但是，分子和细胞。 apelin 功能的机制在很大程度上是未知的，并且 apelin 依赖的细胞串扰肌肉干细胞 (MuSC)、内皮细胞和免疫细胞之间的相互作用，有助于增强肌肉使用斑马鱼作为模型系统，我们将结合新颖的。进行最先进的 apelin 功能丧失和获得研究和使用的药理学遗传学方法单细胞 RNA 测序可识别限制衰老影响的 apelin 下游效应子。提议测试 apelin 作为抗衰老和促再生信号肽的功能并破译细胞该 COBRE 项目包括两种类型的 apelin 在肌肉老化和再生过程中的特定功能。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。和新生成的 Cre/Lox 斑马鱼转基因品系，以确定慢性和基因诱导的肌肉来源的 apelin 影响肌肉衰老的特征（萎缩、衰老、炎症……）。 CRISPR/Cas-9 斑马鱼突变体还将使我们能够测试 apelin 受体激活的功能 MuSC、内皮细胞和巨噬细胞破译肌肉过程中细胞类型特异性 apelin 功能目标 2 将利用最先进的单细胞 RNA 测序揭示一组基因。利用 apelin 受体突变鱼调节 MuSC 向增殖的转变，这种转录组分析还应该能够识别apelin背后的再生因子成功完成这些目标将定义 MuSC 依赖性再生反应中的功能。肌肉衰老过程中多种不同细胞类型中的apelin信号传导，并揭示分子和细胞目标是减轻或逆转与年龄相关的肌肉减少症。