CAREER: Mechanistic Investigations to Enable Rationally Designed Biomanufacturing of Mesenchymal Stem Cell Exosomes

使用患者自身细胞的疗法在治疗包括癌症在内的各种疾病方面显示出巨大的前景。可靠地制造治疗性细胞是一项重大挑战。该项目将确定设计和控制参数，使之成为可能。最初的重点是生产一种基于细胞的伤口愈合疗法。如果成功，所开发的技术可能会在治疗其他危及生命的疾病方面取得突破。一项教育计划将促进高中到研究生阶段的机会和培训。在高中阶段，每年影响数百名学生的渐进式计划将增加研究机会，并促进STEM职业道路的保留。社区外展计划也将得到支持，研究成果将被整合，以加强这些programmes.Establishing新的标准，合理设计的治疗性间充质干细胞/基质细胞（MSC）exosomes的生物制造方法是这个项目的重点。外泌体具有治疗生物活性，包括血管形成。与基于细胞的疗法相关的许多治疗效果现在被归因于来自植入细胞分泌的外来体和其他细胞外囊泡的蛋白质、核酸和/或脂质转移。一般假设是MSC外泌体的产生和治疗生物活性由细胞培养微环境和生产者MSC的状态限定。研究目的是：1）研究血管化生物活性的机制; 2）研究细胞密度对生产的影响机制; 3）开发定量预测标准，以实现外泌体生产的质量控制。如果成功，这项技术将通过为伤口修复、缺血性疾病和其他疾病提供新的治疗选择来影响患者。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Therapies that use a patient's own cells show great promise in the treatment of a variety of diseases, including cancer. Manufacturing therapeutic cells reliably is a major challenge. This project will define design and control parameters to make this possible. The initial focus is on producing a cell-based therapy for wound healing. If successful, the technology that is developed could lead to breakthroughs in treatments for other life-threatening diseases. An education plan will promote opportunities and training at the high school through post-graduate levels. A progressive program at the high school level that impacts hundreds of students per year will increase exposure to research opportunities and promote retention in STEM career paths. Community outreach programs will also be supported, and research findings will be integrated to enhance these programs.Establishing new criteria for rational design of biomanufacturing approaches for therapeutic mesenchymal stem/stromal cell (MSC) exosomes is the focus of this project. Exosomes have therapeutic bioactivity, including vascularization. Many of the therapeutic effects associated with cell-based therapies are now being ascribed to protein, nucleic acid, and/or lipid transfer from exosomes and other extracellular vesicles secreted by implanted cells. The general hypothesis is that MSC exosome production and therapeutic bioactivity are defined by the cell culture microenvironment and the status of producer MSCs. The research objectives are to: 1) investigate the mechanism of vascularization bioactivity; 2) investigate the mechanism of cell density effects on production; and 3) develop quantitative predictive criteria to enable quality control of exosome production. If successful, this technology will impact patients by enabling new therapeutic options for wound repair, and ischemic and other diseases.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.