Predictive and systems modeling of exosome cargo

摘要 心肌梗死后心肌的不良重塑加速了进展， 心衰虽然细胞疗法已经得到了极大的热情， 这些缺点阻碍了长期的功能改善。这些细胞来自 患病个体和免疫原性限制了大多数自体治疗研究。最后是 广泛认为细胞疗法的主要作用是由旁分泌效应物介导的， 细胞本身。 我们已发表的研究表明，大鼠心脏祖细胞（CPC）， 当细胞暴露于缺氧时，外泌体是修复性的， 梗塞此外，我们能够使用计算和 系统生物学最近，我们已经能够从儿科活检中分离出CPC， 显示了心力衰竭模型中细胞治疗的年龄相关变化。初步研究 表明这些外泌体的功能也因年龄和缺氧而异。因此 本提案的目的是检查人类儿科的保护/再生能力， 大鼠缺血再灌注模型中的CPC外泌体。此外，随着大量 患者样本来自各种各样的儿童，我们可以进行多变量分析， 影响各种体内机制的因素。因素包括患者年龄、性别和 暴露于缺氧条件下。最后，我们将通过查看修复性 来自其他细胞类型，CD34+细胞的外泌体，并检查缺氧的机制是否 外泌体功能在不同细胞中是保守的。 完成拟议的研究将确定缺氧外泌体是否是一种 缺血-再灌注损伤的有益治疗，以及确定潜在的患者因素 对这些反应有贡献。

Abstract 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. Our published studies demonstrate that rat cardiac progenitor cells (CPCs) make exosomes, and when cells are exposed to hypoxia, exosomes are reparative following infarction. Moreover, we were able to demonstrate potential pathways using computational and systems biology. Recently, we have been able to isolate CPCs from pediatric biopsies and show age-related changes in cell therapy in a model of heart failure. Preliminary studies demonstrate that these exosomes also vary in function by age and hypoxia. Therefore, the objective of this proposal is to examine the protective/regenerative capacity of human pediatric CPC exosomes in rat models of ischemia-reperfusion. Additionally, with a large number of patient samples from a wide variety of children, 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. Finally, we will expand our model by looking at reparative exosomes from other cell types, CD34+ cells, and examine whether mechanisms of hypoxic exosome function are conserved among different cells. 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.