Functional Activation and Targeting of Exosomes for Regenerative Medicine

再生医学外泌体的功能激活和靶向

• 批准号: 10165690
• 负责人: PRAVEEN GAJENDRAREDDY
• 金额: $ 37.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165690
• 关键词: 3-Dimensional; Affinity; Antibodies; Architecture; Autologous; BMP2 gene; Binding; Biocompatible Materials; Biological Models; Biomimetics; Bone Regeneration; Calvaria; Cancer Biology; Cartilage; Cell Fate Control; Cell Lineage; Cell physiology; Cells; Characteristics; Clinical; Collagen Type I; Defect; Disease; Dosage Forms; Effector Cell; Endocytosis; Engineering; Evaluation; Extracellular Matrix; FDA approved; Fibronectins; Generations; Goals; Gold; Growth Factor; Hardness; Heart; Histology; Hour; ITGA5 gene; Immune response; Immunologics; Immunology; In Vitro; Injury; Integrins; Investigation; Kinetics; Knowledge; Label; Laboratories; Lipids; Liver; Mediating; Mesenchymal Differentiation; Mesenchymal Stem Cells; MicroRNAs; Modeling; Muscle; Nature; Pancreas; Parents; Play; Process; Production; Proteins; RGD (sequence); Rattus; Regenerative Medicine; Role; Signal Transduction; Site; Skin; Specificity; System; Therapeutic; Tissue Engineering; Tissues; Translations; Undifferentiated; base; bone; cell type; dosage; engineered exosomes; exosome; experience; experimental study; genetic information; immunoreaction; in vivo; in vivo evaluation; morphogens; nano; nanoindentation; nanoscale; nanovesicle; osteoblast differentiation; osteogenic; protein expression; scaffold; selective expression; stem cell differentiation; stem cell exosomes; stem cell function; stem cells; tissue regeneration; tool

Summary: Stem Cell Lineage Determination (SCLD) is a necessary and important step required for successful regeneration of tissues lost due to disease or injury. Existing tissue engineering approaches employ the use of growth factors and morphogens along with relevant biomaterials to achieve SCLD. However, this approach to SCLD is limited by several factors such as dosage, delivery, ectopic activity, adverse immunological complications and aberrant differentiation. As a result of these limitations, the single morphogen system has either caused significant clinical complications (from FDA approved growth factors such as BMP2) or has failed to be translationally successful. The need of the hour is a replacement for this single morphogen/growth factor system that is biomimetic in nature and does not pose the same threats to translation. In this regard, the use of exosomes can be beneficial owing to their biomimetic nature, their ability to be endocytosed by recipient cells and their positive immunological reactions. However, two fundamental questions need investigation to aid the use of exosomes as nano biomimetic tools to achieve SCLD in regenerative medicine. They are: 1. Can exosomes be targeted to biomaterials for localized delivery? 2. Can exosomal composition be modified to induce tissue-specific SCLD? This application is an effort to bridge this knowledge gap. We propose to engineer targetability and lineage-specific functionality into exosomes to generate Functionally Activated Targeted Exosomes (FATE). In this application, we will use bone regeneration as a model system to study the generation, evaluation and application of FATE for regenerative medicine. We propose three specific aims to achieve this goal. In Aim 1, we will engineer exosomes with enhanced binding characteristics to ECM proteins type I collagen and Fibronectin to enable biomaterial-mediated site-specific targeting. In Aim 2, we will engineer osteoinductive functionality into the targeting exosomes using two distinct approaches and evaluate the resulting FATE in vitro. In Aim 3, we will evaluate the targeting and functionality of FATE generated in aim 2 in vivo in a critical size rat calvarial defect model. The successful completion of these studies will serve as proof-of-principle that cell-derived nano vesicles (exosomes) can be engineered to possess characteristics required to enhance SCLD for tissue-specific regeneration.

概括： 干细胞谱系测定（SCLD）是成功的必要且重要的步骤 因疾病或受伤而损失的组织的再生。现有的组织工程方法采用 生长因子和形态发生素以及相关生物材料以实现 SCLD。然而，这种方法 SCLD 受到多种因素的限制，例如剂量、递送、异位活性、不良免疫学 并发症和异常分化。由于这些限制，单一形态发生素系统 导致严重的临床并发症（来自 FDA 批准的生长因子，如 BMP2）或失败 获得转化成功。当前需要的是替代这种单一形态发生素/生长因子 该系统本质上是仿生的，不会对翻译造成同样的威胁。在这方面，使用 外泌体的利用可能是有益的，因为它们具有仿生性质，能够被受体内吞 细胞及其阳性免疫反应。然而，有两个基本问题需要调查 帮助使用外泌体作为纳米仿生工具来实现再生医学中的 SCLD。它们是：1. 外泌体可以靶向生物材料进行局部递送吗？ 2. 外泌体成分可以修改为 诱导组织特异性 SCLD？该应用程序旨在弥补这一知识差距。我们建议 将靶向性和谱系特异性功能设计到外泌体中以生成功能激活的 靶向外泌体（FATE）。在此应用中，我们将使用骨再生作为模型系统来研究 再生医学 FATE 的生成、评估和应用。我们提出三个具体目标 实现这一目标。在目标 1 中，我们将设计具有增强的 ECM 蛋白结合特性的外泌体 I 型胶原蛋白和纤连蛋白可实现生物材料介导的位点特异性靶向。在目标 2 中，我们将 使用两种不同的方法将骨诱导功能设计到靶向外泌体中并评估 由此产生的体外命运。在目标 3 中，我们将评估目标中生成的 FATE 的定位和功能 2.体内临界尺寸大鼠颅骨缺损模型。这些研究的成功完成将作为 原理证明细胞源性纳米囊泡（外泌体）可以被设计为具有特性 增强 SCLD 进行组织特异性再生所需。