Predictive and systems modeling of exosome cargo

外泌体货物的预测和系统建模

• 批准号: 10321649
• 负责人: Michael E Davis
• 金额: $ 73.68万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321649
• 关键词: Adult; Affect; Age; Allogenic; Autologous; Biocompatible Materials; Biological Assay; Biological Markers; Biological Models; Biopsy; Blood; CD34 gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Therapy; Cell Transplantation; Cells; Child; Child health care; Childhood; Clinical Trials; Collaborations; Computational Biology; Computer Analysis; Congestive Heart Failure; Data; Diagnostic; Disease; Endothelial Cells; Epigenetic Process; Exposure to; Extracellular Space; Fibroblasts; Fibrosis; Gender; Gene Expression; Gene Expression Regulation; Genetic Transcription; Growth Factor; Heart failure; Human; Hypoxia; Image; In Vitro; Individual; Infarction; Injections; Ischemia; Label; Least-Squares Analysis; Lipoproteins; Matched Group; Measures; Mechanics; Mediating; Methods; MicroRNAs; Modeling; Morbidity - disease rate; Multivariate Analysis; Muscle Cells; Myocardial Infarction; Myocardium; Natural regeneration; Newborn Infant; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Peptide Sequence Determination; Proteins; Publishing; RNA; Rattus; Regenerative capacity; Regression Analysis; Reperfusion Injury; Reperfusion Therapy; Role; Sampling; Signal Transduction; Source; Speed; Surgeon; System; Systems Biology; Therapeutic; Therapy trial; Tissues; age effect; age group; age related; angiogenesis; base; cardiac repair; cardioprotection; cell type; early childhood; effective therapy; exosome; functional improvement; gene therapy; healing; heart function; hemodynamics; horizontal cell; immunogenicity; imprint; improved; improved functioning; in vivo; microvesicles; mortality; normoxia; paracrine; prevent; regeneration potential; regenerative; regenerative cell; repaired; response; sex; stem; stem cell function; stem cells; therapeutic miRNA; uptake

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.

抽象的 心肌梗塞后心肌的不良重塑加速了心肌梗塞的进展 心脏衰竭。尽管细胞疗法受到了极大的热情，但仍有许多 阻碍长期功能改进的缺点。而且，这些细胞来自 患病个体和免疫原性将大多数研究限制为自体治疗。最后，就是 人们普遍认为细胞疗法的主要作用是由旁分泌效应器介导的，而不是 细胞本身。 我们发表的研究表明，大鼠心脏祖细胞 (CPC) 使 外泌体，当细胞暴露于缺氧时，外泌体会进行修复 梗塞。此外，我们能够使用计算和方法来证明潜在的途径 系统生物学。最近，我们已经能够从儿科活检中分离出 CPC， 显示心力衰竭模型中细胞疗法与年龄相关的变化。初步研究 证明这些外泌体的功能也会因年龄和缺氧而变化。因此， 该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 来自各种儿童的患者样本，我们可以进行多变量分析来检查 影响各种体内机制的因素。因素包括患者年龄、性别 暴露于缺氧条件。最后，我们将通过研究修复来扩展我们的模型 来自其他细胞类型、CD34+细胞的外泌体，并检查缺氧机制是否 外泌体的功能在不同细胞之间是保守的。 拟议研究的完成将确定缺氧外泌体是否是一种 对缺血再灌注损伤的有益治疗，以及确定潜在的患者因素 有助于这些反应。

项目成果

Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial.

在左心发育不全综合征双向腔肺吻合术中使用 Lomecel-B 进行心肌内细胞治疗：ELPIS I 期试验。

• 发表时间: 2023-03
• 作者: Kaushal, Sunjay;Hare, Joshua M;Hoffman, Jessica R;Boyd, Riley M;Ramdas, Kevin N;Pietris, Nicholas;Kutty, Shelby;Tweddell, James S;Husain, S Adil;Menon, Shaji C;Lambert, Linda M;Danford, David A;Kligerman, Seth J;Hibino, Narutoshi;Korutla, La
• 通讯作者: Korutla, La

The Effect of Parent Cell Type on Small Extracellular Vesicle-Derived Vehicle Functionality.

亲代细胞类型对小细胞外囊泡衍生载体功能的影响。

• DOI: 10.1002/adbi.202300462
• 发表时间: 2023-12-24
• 期刊: Advanced Biology
• 影响因子: 3.7
• 作者: Sruti Bheri;Hyun;J. Hoffman;Felipe Takaesu;Michael E. Davis
• 通讯作者: Michael E. Davis

Using Statistical Modeling to Understand and Predict Pediatric Stem Cell Function.

使用统计模型来理解和预测儿科干细胞功能。

• DOI: 10.1161/circgen.118.002403
• 发表时间: 2019-05-17
• 期刊: Circulation: Genomic and Precision Medicine
• 作者: Farnaz Shoja;A. George;Udit Agarwal;M. Platt;G. Gibson;Michael E. Davis
• 通讯作者: Michael E. Davis

Knockdown of deleterious miRNA in progenitor cell-derived small extracellular vesicles enhances tissue repair in myocardial infarction.

祖细胞来源的小细胞外囊泡中有害 miRNA 的敲低可增强心肌梗塞的组织修复。

• 发表时间: 2023-03-03
• 影响因子: 13.6
• 作者: Park, Hyun;Hoffman, Jessica R;Brown, Milton E;Bheri, Sruti;Brazhkina, Olga;Son, Young Hoon;Davis, Michael E
• 通讯作者: Davis, Michael E

Customized Loading of microRNA-126 to Small Extracellular Vesicle-Derived Vehicles Improves Cardiac Function after Myocardial Infarction.

将 microRNA-126 定制加载到小型细胞外囊泡衍生载体中可改善心肌梗死后的心脏功能。

• 发表时间: 2023-10-24
• 影响因子: 17.1
• 作者: Bheri, Sruti;Brown, Milton E;Park, Hyun;Brazhkina, Olga;Takaesu, Felipe;Davis, Michael E
• 通讯作者: Davis, Michael E