Heterogeneity of Satellite Cell Populations Play a Role in Improvements in PAD after Exercise Therapy

卫星细胞群的异质性在运动治疗后 PAD 的改善中发挥作用

• 批准号: 10571873
• 负责人: Laura Marie Hansen
• 金额: $ 69.24万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571873
• 关键词: Ablation; Affect; Aftercare; American; Amputation; Animals; Antihypertensive Agents; Area; Arterial Fatty Streak; Automobile Driving; Biological; Biology; Blood Platelets; Blood Vessels; Blood flow; Cardiovascular system; Cell Count; Cells; Cellular biology; Clinical; Cre lox recombination system; Cytokine Signaling; Data; Development; Disease; Disease Progression; Exercise; Exercise Therapy; Gene Expression; Genetic Transcription; Goals; Growth; Growth Factor; Health; Heterogeneity; Human; Hypoxia; Impairment; In Vitro; Ischemia; Lactic acid; Limb structure; Mediating; Mediator; Medical; Modeling; Mus; Muscle; Muscle satellite cell; Nature; Operative Surgical Procedures; Pain; Paracrine Communication; Pathology; Patient Isolation; Patient-Focused Outcomes; Patients; Perfusion; Peripheral arterial disease; Persons; Phenotype; Play; Population; Process; Proliferating; Proteins; Quality of life; Recommendation; Recovery; Reporting; Research; Research Priority; Risk Factors; Role; Running; Sampling; Skeletal Muscle; Skeletal Muscle Satellite Cells; Stimulus; Symptoms; Tamoxifen; Testing; Therapeutic; Tissue Sample; Tissues; Walking; Work; cell motility; claudication; cost; cytokine; density; effective therapy; evidence base; exercise intervention; exercise program; exercise regimen; exercise training; functional improvement; histological stains; human tissue; improved; in vivo; inducible Cre; limb ischemia; migration; mortality; mouse model; muscle physiology; non-healing wounds; novel; patient response; preconditioning; prevent; programs; repaired; response; response to injury; satellite cell; single cell sequencing; single-cell RNA sequencing; treatment strategy

Abstract Peripheral artery disease (PAD) is a major health problem worldwide. Patients with the disease have atherosclerotic lesions which impair blood flow to their limbs resulting in complications such as non-healing wounds and amputations as well as pain and decreased quality of life. While many medical therapies have been established to slow disease progression through controlling risk factors, the two most effective treatments at improving a patient’s status are surgical or endovascular repair and supervised exercise therapy. While exercise is an ideal treatment due to its lower cost and non-invasive nature, the mechanisms by which it improves patient outcomes are still not known preventing the development of an ideal therapeutic strategy. This proposal investigates a novel mechanism by which skeletal muscle satellite cells mediate these observed improvements. Preliminary data shows that satellite cells generate several different proteins which are associated with vascular growth and drive migration in vascular cells. Histological staining of human samples shows that satellite cells increase in patients that see improvements with exercise and the presence of satellite cells appears to be critical for recovery in an exercise preconditioning murine model. Aim 1 will investigate the causal relationship between satellite cells and exercise mediated recovery using an murine model in which satellite cells are selectively ablated. Aim 2 will use single cell sequencing to investigate the heterogeneity of satellite cells in response to exercise and determine which stimuli and which specific expression profiles are the most vasculogenic. Finally, Aim 3 will quantify the expression changes and heterogeneity in satellite cells from PAD patients isolated before and after supervised exercise therapy. The goal of this aim is to determine how differences in satellite cell populations correlate with clinical responses in the patients. The ultimate goal of this project is to understand the biology and response of satellite cells in response to exercise to help develop more effective exercise regimens for patients with PAD.

摘要 外周动脉疾病(PAD)是世界范围内的主要健康问题。患有这种疾病的患者有 动脉粥样硬化损害了流向四肢的血液，导致并发症，如无法愈合 伤口和截肢以及疼痛和生活质量下降。虽然许多医学疗法已经被 建立了通过控制风险因素来减缓疾病进展的两种最有效的治疗方法 改善患者状态的方法是手术或血管内修复以及有监督的运动疗法。在锻炼时 是一种理想的治疗方法，因为它的低成本和非侵入性，以及它改善患者的机制 结果仍不清楚，阻碍了理想治疗策略的发展。这项建议 研究了一种新的机制，骨骼肌卫星细胞通过它来调节这些观察到的改善。 初步数据显示，卫星细胞会产生几种与血管有关的不同蛋白质。 在血管细胞中生长和驱动迁移。人类样本的组织学染色显示，卫星细胞 运动和卫星细胞的存在改善的患者的增加似乎是关键 用于运动预适应小鼠模型的康复。目标1将调查两者之间的因果关系 在小鼠模型中，卫星细胞和运动介导的康复 消融了。AIM 2将使用单细胞测序来研究卫星细胞的异质性 锻炼并确定哪些刺激和哪些特定的表达模式是最具血管生成能力的。最后， 目的3将量化PAD患者分离的卫星细胞的表达变化和异质性 并在监督下进行运动治疗后。这一目标的目的是确定卫星细胞的差异 人群与患者的临床反应相关。这个项目的最终目标是了解 卫星细胞对运动反应的生物学和反应，以帮助开发更有效的运动 PAD患者的治疗方案。