Collaborative Research: Investigating the role and interplay of microenvironment, manufacturing, and metabolism on MSC production of extracellular vesicles

合作研究：研究微环境、制造和代谢对 MSC 细胞外囊泡生产的作用和相互作用

• 批准号: 2305875
• 负责人: Donald Griffin
• 金额: $ 20万
• 依托单位: University of Virginia Main Campus
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2305875&HistoricalAwards=false
• 关键词: Collaborative; Research; Investigating; role; interplay

Mesenchymal stromal cells (MSCs) are isolated from bone marrow and fat cells. While they are not stem cells, they exhibit a similar ability to differentiate into many types of cells. That ability forms the basis for developing treatments for a variety of diseases. MSCs also generate extracellular vesicles (EVs). The EVs transport bioactive molecules that prompt cellular-level responses. It is difficult to manufacture EVs reproducibly. This limits its current therapeutic potential. Changes in local conditions impact MSC-EV production and function. Understanding those impacts is the focus of this project. The project will also promote STEM participation of students from underrepresented groups.Many challenges contribute to the lack of successful MSC-EV clinical translation. MSC heterogeneity is a key issue. There are no effective critical quality attributes (CQAs) that predict how a given batch of EVs will perform. There are also no standardized manufacturing approaches for EVs. In addition, there is a knowledge gap regarding the effects of scaling EV manufacturing with respect to 2D vs. 3D environments. The overall goals of this project are to understand how 3D structure affects EV production and to identify metabolic pathways controlling this response. To accomplish these goals, the project team will: 1) investigate the effects of 3D hydrogel microenvironments on EV function, 2) determine the effects of manufacturing strategies on EVs, and 3) define metabolic changes associated with EV production. It is anticipated that the mechanisms identified will have relevance for MSC-EVs for different therapeutic applications and for EVs generated by other cell types.This project is jointly supported by the Cellular and Biochemical Engineering Program in ENG/CBET and the Systems and Synthetic Biology Program in BIO/MCB.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

间充质基质细胞（MSC）分离自骨髓和脂肪细胞。虽然它们不是干细胞，但它们表现出类似的分化成多种类型细胞的能力。这种能力构成了开发各种疾病治疗方法的基础。 MSC还产生细胞外囊泡（EV）。EV运输促进细胞水平反应的生物活性分子。 难以可重复地制造EV。这限制了其目前的治疗潜力。当地条件的变化会影响MSC-EV的生产和功能。了解这些影响是本项目的重点。该项目还将促进来自代表性不足群体的学生参与STEM。许多挑战导致缺乏成功的MSC-EV临床翻译。MSC异质性是一个关键问题。没有有效的关键质量属性（CQA）来预测给定批次的EV将如何执行。电动汽车也没有标准化的制造方法。此外，关于电动汽车制造在2D与3D环境中的影响，还存在知识差距。 该项目的总体目标是了解3D结构如何影响EV生产，并确定控制这种反应的代谢途径。为了实现这些目标，项目团队将：1）研究3D水凝胶微环境对EV功能的影响，2）确定制造策略对EV的影响，3）定义与EV生产相关的代谢变化。预计所确定的机制将与用于不同治疗应用的MSC-EV以及由其他细胞类型产生的EV相关。该项目由ENG/CBET的细胞和生化工程项目以及BIO/该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准。