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）从骨髓和脂肪细胞中分离出来。尽管它们不是干细胞，但它们具有分化为多种细胞的类似能力。这种能力构成了开发各种疾病治疗的基础。 MSC还产生细胞外囊泡（EV）。电动汽车转运生物活性分子，这些分子促使细胞级反应。 很难可重复地生产电动汽车。这限制了当前的治疗潜力。当地条件的变化会影响MSC-EV的产生和功能。了解这些影响是该项目的重点。该项目还将促进代表性不足的学生的STEM参与。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。没有有效的临界质量属性（CQA）可以预测给定的一批电动汽车的执行方式。电动汽车也没有标准化的制造方法。此外，关于缩放电动汽车制造对2D与3D环境的影响存在知识差距。 该项目的总体目标是了解3D结构如何影响EV生产并确定控制此反应的代谢途径。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）确定制造策略对电动汽车的影响，3）定义与EV生产相关的代谢变化。可以预料，所确定的机制将与MSC-EVS有关不同的治疗应用以及其他细胞类型产生的EVS具有相关性。该项目由ENG/CBET中的蜂窝和生物化学工程计划共同支持，系统和生物化学工程计划以及系统和合成计划在BIO/MCB中都通过Intervients Intervientional奖，反映了NSF的基础宣传，并以DEEM的构建为基础。和更广泛的影响审查标准。