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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的外周动脉疾病（PAD）是全世界患者面临的一个主要健康问题。动脉粥样硬化病变会损害四肢的血液流动，导致不愈合等并发症尽管许多药物治疗已导致伤口和截肢以及疼痛和生活质量下降。通过控制危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手术或血管内修复以及运动时的监督运动疗法。由于其较低的成本和非侵入性的性质，它是一种理想的治疗方法，它可以改善患者的机制结果仍然未知，阻碍了理想治疗策略的发展。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与血管相关的不同蛋白质人类样本的组织学染色显示卫星细胞的生长和驱动迁移。看到运动改善的患者数量增加，卫星细胞的存在似乎至关重要为了在运动预处理小鼠模型中恢复，目标 1 将研究之间的因果关系。使用小鼠模型进行卫星细胞和运动介导的恢复，其中卫星细胞被选择性地目标 2 将使用单细胞测序来研究卫星细胞响应的异质性。锻炼并确定哪些刺激和哪些特定表达谱最具血管生成性。目标 3 将量化之前分离的 PAD 患者卫星细胞的表达变化和异质性在监督运动治疗后，该目的的目的是确定卫星细胞的差异。该项目的最终目标是了解患者中具有相关临床反应的人群。卫星细胞对运动的生物学和反应有助于开发更有效的运动 PAD 患者的治疗方案。