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: 10367684
• 负责人: Laura Marie Hansen
• 金额: $ 65.3万
• 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/10367684
• 关键词: Affect; Aftercare; American; Amputation; Animals; Antihypertensive Agents; Area; Arterial Fatty Streak; Automobile Driving; Biological; Biology; 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 of activation protein; Medical; Modeling; Mus; Muscle; Muscle satellite cell; Nature; Operative Surgical Procedures; Pain; Paracrine Communication; Pathology; Patient-Focused Outcomes; Patients; Perfusion; Peripheral arterial disease; Persons; Phenotype; Play; Population; Process; Proteins; Quality of life; Recovery; Reporting; Research; Research Priority; Risk Factors; Role; Running; Sampling; Skeletal Muscle; Skeletal Muscle Satellite Cells; Stimulus; Supervision; 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; histological stains; human tissue; improved; improved functioning; in vivo; 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.

抽象的 周围动脉疾病（PAD）是全球主要的健康问题。患有疾病的患者 动脉粥样硬化病变会损害血液流向四肢的流动，导致并发症，例如非污染 伤口和截肢以及疼痛和改善的生活质量。虽然许多医疗疗法已经 建立以通过控制危险因素缓慢疾病进展的建立，这两种最有效的治疗方法 改善患者的状态是手术或血管内修复和监督运动疗法。运动时 由于其成本较低和非侵入性，它是一种理想的治疗方法，其改善患者的机制 结果仍然不知道阻止理想的治疗策略的发展。这个建议 研究了一种新型机制，骨骼肌卫星细胞介导了这些观察到的改善。 初步数据表明，卫星细胞会产生几种与血管相关的不同蛋白质 血管细胞中的生长和驱动迁移。人类样品的组织学染色表明卫星细胞 通过运动和卫星细胞的存在改善的患者增加似乎很关键 用于在运动预处理鼠模型中恢复。 AIM 1将研究之间的因果关系 卫星细胞和使用鼠模型进行卫星细胞有选择的鼠模型进行介导的恢复 消融。 AIM 2将使用单细胞测序来研究卫星细胞的异质性。 锻炼并确定哪种刺激以及哪些特定表达谱是最血管生成的。最后， AIM 3将量化以前分离的PAD患者的卫星细胞的表达变化和异质性 并在有监督的运动疗法之后。该目标的目的是确定卫星电池的差异 种群与患者的临床反应相关。该项目的最终目标是了解 卫星细胞对运动的生物学和反应，以帮助开发更有效的运动 PAD患者的方案。