Mechanisms of extracellular vesicle biogenesis that regulate wound healing

调节伤口愈合的细胞外囊泡生物发生机制

基本信息

批准号：
10622982
负责人：
Brian P Eliceiri
金额：
$ 18.46万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

项目摘要

SUMMARY Resolution in skin wound healing is coordinated by intercellular communication processes that include extracellular vesicles (EVs) containing biologically active protein and nucleic acid. In injury models, EVs have been shown to be important mediators of tissue repair, although the mechanisms underlying the formation of specific EV subsets, loading of EV payloads, and cell- type specific EV uptake remain poorly understood. We address this knowledge gap with a comprehensive genetic approach to modify the regulation of EV biogenesis to change the EV Profile, Payload and Activity in cutaneous wound models that have well-defined biological relevance. We have recently established that genetic tools regulating EV biogenesis `re-program' EV payload. Moreover, over-expression of specific pro-reparative payloads that were identified by mass spectrometry can be engineered and delivered to promote resolution in models of impaired wound healing. With a focus on the discovery of novel EV mediators of crosstalk between immune and epithelial cells in the wound bed, we have focused on the biology of EVs in mediating intercellular signaling in EVs formation (Project 1-EV Biogenesis), the engineering of biologically active payloads (Project 2-EV Payloads), and identifying specific cell types that internalize EVs in the wound bed (Project 3-EV Uptake). Together, these Projects address the over-arching goals of creating therapeutic EVs with a systematic approach that is optimized for specific cell types based on an understanding of 1) How and where EVs are made?; 2) How EVs are loaded and whether they are biologically active ?; and 3) Which cells uptake EVs to promote durable tissue repair.

概括皮肤伤口愈合的解决是通过细胞间通讯过程来协调的包括含有生物活性蛋白和核酸的细胞外囊泡（EV）。受伤中模型中，EV 已被证明是组织修复的重要介质，尽管特定 EV 子集的形成、EV 有效负载的加载和小区的潜在机制特定类型电动汽车的使用情况仍知之甚少。我们通过以下方法解决这一知识差距综合遗传方法来修改 EV 生物发生的调控以改变 EV 具有明确生物学特性的皮肤伤口模型的轮廓、有效负载和活动关联。我们最近建立了调节 EV 生物发生的遗传工具“重新编程” 电动汽车有效载荷。此外，已确定的特定促修复有效负载的过度表达通过质谱分析可以设计和交付以提高模型中的分辨率伤口愈合受损。重点是发现新型 EV 串扰介质在伤口床中的免疫细胞和上皮细胞之间，我们重点研究了 EV 的生物学介导 EV 形成中的细胞间信号传导（项目 1-EV Biogenesis），生物活性有效负载（项目 2-EV 有效负载），并识别特定的细胞类型将 EV 内化到伤口床中（项目 3-EV 摄取）。这些项目共同解决了通过优化的系统方法创建治疗性 EV 的总体目标基于以下理解的特定细胞类型：1）电动汽车的制造方式和地点？； 2) 电动汽车如何是否有负载以及它们是否具有生物活性？ 3) 哪些细胞吸收 EV 来促进持久的组织修复。