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（peripheral artery disease，PAD）是世界范围内的一个主要健康问题。患有这种疾病的患者 动脉粥样硬化损伤损害了流向他们肢体的血流，导致并发症， 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 通过控制风险因素来减缓疾病进展，这是两种最有效的治疗方法， 改善患者状况的方法是外科手术或血管内修复和监督运动疗法。虽然运动 是一种理想的治疗方法，由于其成本较低，无创性，其改善患者的机制， 结果仍然未知，妨碍了理想治疗策略的发展。这项建议 研究了骨骼肌卫星细胞介导这些观察到的改善的新机制。 初步数据表明，卫星细胞产生几种不同的蛋白质，这些蛋白质与血管生成有关。 生长并驱动血管细胞的迁移。人类样本的组织学染色显示卫星细胞 随着运动和卫星细胞的出现， 用于在运动预处理小鼠模型中的恢复。目标1将调查以下因素之间的因果关系： 卫星细胞和运动介导的恢复，使用小鼠模型，其中选择性地 消融。Aim 2将使用单细胞测序来研究卫星细胞的异质性， 运动和确定哪些刺激和哪些特定的表达谱是最血管生成的。最后， 目的3将定量之前分离的PAD患者卫星细胞的表达变化和异质性， 在有监督的运动疗法之后。这一目标的目的是确定卫星细胞中的差异 人群与患者的临床反应相关。这个项目的最终目标是了解 生物学和卫星细胞对运动的反应，以帮助开发更有效的运动 PAD患者的治疗方案。