CPC Excosomes for Cardiac Therapy

用于心脏治疗的 CPC 外泌体

• 批准号: 8903585
• 负责人: Michael E Davis
• 金额: $ 43.57万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903585
• 关键词: Adult; Affect; Age; Allogenic; Autologous; Biocompatible Materials; Biodistribution; Biological Assay; Biological Markers; Blood; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Therapy; Cell Transplantation; Cell physiology; Cells; Child; Chronic; Clinical Trials; Collaborations; Computer Analysis; Data; Disease; Endothelial Cells; Epigenetic Process; Exposure to; Extracellular Space; Fibroblasts; Fibrosis; Gender; Gene Expression; Gene Expression Regulation; Growth Factor; Healed; Health; Healthcare; Heart failure; Human; Hypoxia; Individual; Infarction; Injection of therapeutic agent; Ischemia; Label; Least-Squares Analysis; Lipoproteins; Measures; Mechanics; Mediating; Mesenchymal Stem Cells; Methods; MicroRNAs; Modeling; Molecular Profiling; Morbidity - disease rate; Multivariate Analysis; Myocardial Infarction; Myocardium; Natural regeneration; Newborn Infant; Operative Surgical Procedures; Outcome; Output; Patients; Pattern; Proto-Oncogene Protein c-kit; Publishing; Rattus; Regression Analysis; Reperfusion Injury; Reperfusion Therapy; Role; Sampling; Speed; Stem cells; Surgeon; System; Testing; Therapeutic; Tissues; Toddler; Tube; age effect; age group; angiogenesis; base; cardiac repair; cell type; early childhood; effective therapy; extracellular; functional improvement; gene therapy; healing; hemodynamics; horizontal cell; immunogenicity; imprint; improved; improved functioning; in vivo; in vivo imaging; meetings; mortality; paracrine; prevent; regenerative; repaired; residence; response; stem

DESCRIPTION (provided by applicant): Adverse remodeling of the myocardium after myocardial infarction speeds progression to heart failure. While cell therapy has been met with great enthusiasm, there are numerous shortcomings that prevent long-term functional improvements. Moreover, these cells come from diseased individuals and immunogenicity limits most studies to autologous therapy. Finally, it is widely believed that the main effect of cell therapy is mediated by paracrine effectors and not the cells themselves. We have isolated rat and human cardiac progenitor cells that are cardiac-derived, express c-kit, do not express any markers of cardiogenic lineage, but can differentiate in to all cardiac cell types. These cells basally release microRNA (miR) in to the extracellular space. When treated with hypoxic conditions, these cells increase cardioprotective miRs within exosomes. Preliminary studies demonstrate that these hypoxic exosomes enhance endothelial cell tube formation and decrease fibrotic gene expression in fibroblasts. Therefore, the objective of this proposal is to examine the protective/regenerative capacity of these exosomes in rat models of ischemia-reperfusion. Additionally, with a large number of patient samples from children and adults, we can perform multivariate analysis to examine the factors that affect various in vivo mechanisms. Factors include patient age, gender, and exposure to hypoxic conditions. Completion of the proposed studies will determine whether hypoxic exosomes are a beneficial therapy for ischemia-reperfusion injury, as well as determine potential patient factors that contribute to these responses.

描述(由申请人提供)：心肌梗死后心肌的不良重塑加速进展为心力衰竭。虽然细胞疗法受到了极大的欢迎，但仍有许多缺点阻碍了长期的功能改善。此外，这些细胞来自患病的个体，免疫原性将大多数研究限制在自体治疗上。最后，人们普遍认为细胞治疗的主要作用是由旁分泌效应器介导的，而不是细胞本身。我们已经分离了大鼠和人类的心脏祖细胞，它们是心脏来源的，表达c-kit，不表达任何心源性血统的标志，但可以分化为所有类型的心脏细胞。这些细胞将microRNA(MiR)基本释放到细胞外空间。当在低氧条件下处理时，这些细胞会增加外体内的心脏保护MIR。初步研究表明，这些低氧外切体可促进成纤维细胞内皮细胞管的形成，降低成纤维细胞纤维化基因的表达。因此，这项建议的目的是检测这些外切体在大鼠缺血再灌注模型中的保护/再生能力。此外，利用来自儿童和成人的大量患者样本，我们可以进行多变量分析，以检查影响体内各种机制的因素。因素包括患者的年龄、性别和暴露在低氧条件下。拟议研究的完成将确定低氧外切体是否对缺血再灌注损伤是一种有益的治疗方法，以及确定影响这些反应的潜在患者因素。