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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10622982
• 关键词: Address; Biogenesis; Biological; Biology; Biomedical Engineering; Cells; Engineering; Epithelial Cells; Epithelium; Genetic; Goals; Immune; Impaired wound healing; Inflammation; Injury; Intercellular Communication Process; Knowledge; Macrophage; Mass Spectrum Analysis; Mediating; Mediator; Modeling; Nucleic Acids; Phase; Proteins; Regulation; Resolution; Signal Transduction; Site; Skin wound healing; Stromal Cells; Therapeutic; Vesicle; Wound models; cell type; extracellular vesicles; genetic approach; novel; overexpression; programs; skin wound; tissue repair; tool; uptake; wound; wound bed; wound closure; wound healing

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 皮肤伤口愈合中的分辨率通过细胞间沟通过程协调 包括含有生物活性蛋白和核酸的细胞外囊泡（EV）。受伤 模型，EV已被证明是组织修复的重要介质，尽管 特定EV子集形成，EV有效载荷的加载和细胞的基础机制 特定的EV摄取量仍然很少了解。我们通过 综合遗传方法修改EV生物发生的调节以改变EV 皮肤伤口模型的轮廓，有效载荷和活动，具有明确定义的生物学 关联。我们最近确定，调节EV生物发生的遗传工具“重新编程” EV有效载荷。此外，已识别的特定依靠有效载荷的过表达 可以通过质谱法进行设计和交付，以促进模型中的分辨率 伤口愈合受损。重点是发现新颖的串扰电动汽车介质 在伤口床的免疫和上皮细胞之间，我们专注于电动汽车的生物学 介导电动汽车形成中的细胞间信号传导（项目1-EV生物发生），工程 生物主动有效载荷（项目2-ev有效载荷），并确定特定的单元类型 在伤口床中内化电动汽车（项目3-EV吸收）。这些项目一起解决了 通过系统的方法来创建治疗性电动汽车的超大目标 基于对1）如何以及在何处制造电动汽车的特定细胞类型？ 2）电动汽车如何 加载以及它们是否具有生物活性？ 3）哪些细胞吸收EV促进 耐用的组织修复。