Regulation of Muscle Fibrosis in Response to Injury and Aging

调节肌肉纤维化以应对损伤和衰老

• 批准号: 8811007
• 负责人: THOMAS A. RANDO
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811007
• 关键词: 3' Untranslated Regions; Activities of Daily Living; Acute; Adult; Affect; Age; Aging; Cell Culture Techniques; Cell Therapy; Cells; Cicatrix; Clinical; Collagen; Connective Tissue; Data; Degenerative Disorder; Deposition; Development; Disease; Effectiveness; Exhibits; Fatty acid glycerol esters; Fibrosis; Functional disorder; Genes; Goals; Health; In Vitro; Infiltration; Injury; Introns; Investigation; Lead; Ligands; Link; Mission; Molecular; Muscle; Muscle Contraction; Muscle function; Muscle satellite cell; Natural regeneration; PDGFRB gene; Pancreas; Pathology; Pathway interactions; Pattern; Phosphorylation; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Polyadenylation; Population; Population Study; Post-Transcriptional Regulation; Production; Proteins; Quality of life; RNA Sequences; Recovery; Regulation; Role; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Skeletal muscle injury; Skin; Specificity; Testing; Therapeutic; Transcript; Transplantation; Trauma; Untranslated Regions; Variant; Veterans; Work; age related; aged; base; cell behavior; combat; experience; improved; in vivo; indexing; inhibitor/antagonist; insight; muscle aging; muscle regeneration; muscle strength; prevent; progenitor; public health relevance; regenerative; response; response to injury; skeletal; stem cell biology; stem cell population; therapeutic development; therapy development; tissue repair; tool; transcriptome sequencing

Aging skeletal muscle exhibits a marked decrease in regenerative capabilities, which is associated with fatty infiltration and the deposition of fibrous connective tissue. This fibrotic deposition is particularly harmful because it interferes with proper muscle contraction. While this phenomenon has been widely documented, the mechanisms underlying this fibrosis are still under investigation. Unlike aged muscle, young muscle does not develop permanent fibrosis. However, it does display transient collagen deposition after acute injury. An understanding of the molecular pathways that trigger this collagen accumulation in young muscle as well as their dysregulation with age will be important for the development of therapeutics to prevent the progression of this pathology. Several studies have linked fibrosis to increased signaling of the platelet-derived growth factor (PDGF) pathway. Recently, it was shown that PDGF receptor alpha (PDGFR¿) signaling promotes proliferation and differentiation of a population of muscle-resident fibroadipogenic progenitors (FAPs), which have been hypothesized to contribute to accumulation of both fibrous connective tissue and fat in muscle with age. Our preliminary data suggest that PDGFR¿ signaling is upregulated in FAPs upon muscle injury and that changes in this signaling pathway may influence their fibrogenic differentiation potential. We hypothesize that PDGFR¿ signaling in FAPs is responsible for their activation during muscle regeneration and that overstimulation of this pathway causes increased fibrosis. We will examine this hypothesis by studying PDGFR¿ signaling during normal muscle regeneration and testing whether the stimulation and inhibition of the pathway affects the development of fibrosis, and how depletion of FAPs alters muscle regenerative capacity (Aim 1). We will examine how the levels of PDGFR¿ signaling change in muscle with age and we will investigate whether inhibiting signal transduction results in a reduction in fibrosis accumulation in aged muscle (Aim 2). Finally, we will explore the mechanisms by which the PDGFR¿ transcript is regulated (Aim 3). Our preliminary data suggest that multiple variants of the PDGFR¿ transcript are produced that that these variants may alter the ultimate expression of the PDGFR¿ protein. We will study how PDGFR¿ is regulated post-transcriptionally through an analysis of polyadenylation site selection. Through our examination of this newly-discovered population of FAPs, we aim to understand the mechanisms that guide their activation in healthy muscle to assess their role in the fibrotic pathology of aged muscle. Our investigation will both allow for the production of new experimental tools to study this population and lend insight into therapeutic strategies to prevent age-related fibrosis. This will have direct relevance to Veterans who are suffering from skeletal muscle injuries, injuries that have limited their functional capacity and that, to date, have no hope of further recovery. This will also be directly relevant to our aging Veteran population, many of whom experience decreasing muscle strength and increasing muscle stiffness, limiting their normal activities. Our goal is to develop a therapeutic approach to muscle tissue repair based upon a deep understanding of the basic stem cell biology and a firm commitment to the clinical/translational mission to improve the health and quality of life of Veterans whose function is limited by the lack of effective therapeutic options.

老化的骨骼肌表现出明显的再生能力下降，这与 脂肪浸润和纤维结缔组织的沉积。这种纤维化沉积物特别有害 因为它会干扰适当的肌肉收缩。虽然这种现象已被广泛记载，但 该纤维化的基础机制仍在研究中。与年龄的肌肉不同，年轻的肌肉没有 发展永久性纤维化。但是，它确实显示出急性损伤后的瞬时胶原蛋白沉积。一个 了解触发这种胶原蛋白在Young肌肉以及的分子途径以及 随着年龄的增长，他们的失调对于制定理论以防止的发展很重要 这种病理。几项研究已将纤维化与血小板衍生生长因子的信号增加联系起来 （PDGF）途径。最近，显示PDGF受体α（PDGFR¿）信号促进了增殖 和肌肉居民纤维富集祖先（FAP）的种群的分化， 假设有助于随着年龄的增长而在肌肉中纤维连接的组织和脂肪的积累。我们的 初步数据表明，PDGFR¿信号在肌肉损伤时更新了FAP，并且会改变 在此信号通路中，可能会影响其纤维化分化潜力。我们假设PDGFR¿ FAPS中的信号导致它们在肌肉再生过程中的激活，并且过度刺激 途径会导致纤维化增加。 我们将通过研究正常肌肉再生期间的PDGFR？ 测试刺激和抑制途径是否会影响纤维化的发展，以及如何 FAP的耗竭会改变肌肉再生能力（AIM 1）。我们将研究PDGFR¿的水平 随着年龄的增长，肌肉的信号变化，我们将研究抑制信号转导的抑制是否导致A 老年肌肉纤维化积累的减少（AIM 2）。最后，我们将探讨 pDGFR¿成绩单受调节（AIM 3）。我们的初步数据表明PDGFR¿的多种变体 转录本的产生是这些变体可能会改变PDGFR？蛋白的最终表达。我们 将通过分析聚腺苷酸化位点的选择来研究PDGFR？在转录后如何调节。 通过检查新发现的FAP人群，我们旨在了解 指导其在健康肌肉中激活以评估其在老年纤维化病理中的作用的机制 肌肉。我们的投资都将允许生产新的实验工具来研究这一人群 并采用治疗策略，以防止与年龄相关的纤维化。这将与 遭受骨骼肌损伤的退伍军人，受伤的功能能力和 迄今为止，这没有进一步康复的希望。这也将与我们的老兵直接相关 人口，其中许多人经历降低肌肉力量和增加肌肉僵硬，限制 他们的正常活动。我们的目标是开发一种治疗方法来基于 对基本干细胞生物学的深入了解以及对临床/翻译任务的坚定承诺 改善由于缺乏有效疗法而限制的退伍军人的健康和生活质量 选项。