CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome

职业：基于亲和力的工程生物材料用于利用干细胞分泌组

• 批准号: 2237240
• 负责人: Marian Hettiaratchi
• 金额: $ 60万
• 依托单位: University of Oregon Eugene
• 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: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2237240&HistoricalAwards=false
• 关键词: CAREER; Engineered; Affinity; Based; Biomaterials

Non-technical AbstractStem cells hold tremendous promise for the field of regenerative medicine due to their potential to repair injured and diseased tissues. However, the promise of stem cells has not been fully realized, as the majority of stem cells transplanted into the body after injury die rapidly after transplantation. Despite their fate, these stem cells still often manage to have a small positive impact on the damaged tissues into which they are transplanted. This healing response is partly due to the proteins secreted by the stem cells into the surrounding injury environment, which can reduce inflammation and make the environment more hospitable for the infiltration of host cells to regenerate the injured tissue. However, proteins typically also do not remain within the injury site for long periods of time, making their effects short-lived. The goal of this CAREER proposal is to develop biomaterials to capture and concentrate these potent cell-secreted proteins to enhance and prolong their therapeutic effects beyond the initial period of stem cell survival. These biomaterials will be engineered to only capture specific proteins of interest from a complex mixture of cell-secreted proteins, thereby allowing them to act as sieves – enriching therapeutic proteins without trapping ineffective proteins. Toward broad societal impact, the ability to selectively enrich regenerative proteins from complex mixtures could transform the therapeutic potential of stem cell transplantation with implications for treating many diseases and injuries, including musculoskeletal injuries, cardiovascular disease, and spinal cord injury. This highly interdisciplinary project requires participation by students interested in bioengineering, chemistry, biology, and human physiology, and will engage students across multiple departments at the University of Oregon in both bioengineering research and education. An inclusive bioengineering education course will be developed to give students from a variety of disciplines the skills necessary to develop sustainable bioengineering outreach activities that can, in turn, be used to promote pathways to bioengineering for K-12 students underrepresented in science, technology, engineering, and math (STEM). By increasing access to bioengineering curriculum at multiple levels (K-12, undergraduate, and graduate students), the proposed work will diversify the pool of talented scientists and engineers with the skills and desire to engage in interdisciplinary bioengineering research.Technical AbstractMesenchymal stem/stromal cells (MSCs) secrete proteins that can mediate the immune response to injury and stimulate tissue repair. However, poor viability of transplanted MSCs can limit long-term therapeutic effects. Harnessing the regenerative potential of stem cells through the proteins they secrete (i.e., the “secretome”) represents a recent paradigm shift in the field of tissue engineering. Biomaterials can be used to sequester and prolong the presentation of secreted proteins beyond the initial period of cell survival. Yet, current biomaterials have a limited ability to selectively sequester specific target proteins from complex protein mixtures. The goal of this CAREER proposal is to develop a library of affinity-based biomaterials that can selectively sequester and present therapeutic proteins secreted by MSCs. Several key innovations will be employed herein, including the use of directed evolution to identify high-specificity affinity interactions between target proteins and materials, and the use of bio-transport modeling to predict the effects of protein-material affinity interactions and protein secretion rates on overall protein sequestration, thereby enabling the optimization of biomaterials for protein sequestration. This highly interdisciplinary project requires participation by trainees interested in bioengineering, chemistry, biology, and human physiology, and will engage students across multiple departments at the University of Oregon in both bioengineering research and education. An inclusive bioengineering education course will be developed to increase access to bioengineering curriculum and give students from a variety of disciplines the professional and pedagogical skills to develop sustainable bioengineering outreach activities that can, in turn, be used to promote pathways to bioengineering for K-12 students underrepresented in STEM.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.

非技术抽象系统细胞因修复受伤和解散的组织的潜力而对再生医学领域具有巨大的希望。但是，由于损伤后，大多数干细胞在移植后迅速死亡，因此干细胞的承诺尚未完全实现。尽管命运命运，这些干细胞仍然经常对被移植的受损组织产生微小的积极影响。这种愈合反应部分是由于干细胞分泌到周围损伤环境中的蛋白质，这可以减少感染，并使环境更容易渗透宿主细胞以再生受伤的组织。但是，蛋白质通常也不会长时间保留在损伤部位内，从而使它们的影响短暂。该职业建议的目的是开发生物材料，以捕获和集中这些潜在的细胞分泌蛋白，以增强和延长其治疗作用，超过干细胞存活的最初时期。这些生物材料将被设计为仅从细胞分泌蛋白的复杂混合物中捕获特定感兴趣的蛋白质，从而使它们充当筛子 - 富集治疗蛋白而不会捕获无效的蛋白质。面向广泛的社会影响，从复杂混合物中选择性丰富再生蛋白的能力可以改变干细胞移植的治疗潜力，对治疗许多疾病和损伤的影响，包括肌肉骨骼损伤，心血管疾病和脊髓损伤。这个高度的跨学科项目需要对生物工程，化学，生物学和人类生理学感兴趣的学生参与，并将吸引俄勒冈大学多个系的学生参与生物工程研究和教育。将开发包容性的生物工程教育课程，以使来自各种学科的学生提供开发可持续的生物工程外展活动所必需的技能，而K-12学生则可以促进对科学，技术，工程和数学（STEM）中代表性不足的K-12学生的生物工程途径。通过增加在多个级别（K-12，本科和研究生）中获得生物工程课程的访问，拟议的工作将使有才华的科学家和工程师的群体多样化，具有从事跨学科生物工程研究的技能和愿望。技术型摘要型干细胞/间质细胞（MSCS）刺激蛋白质，以促进刺激性抗衡性，以促进促进蛋白质和刺激性抗衡。但是，移植的MSC的生存能力差会限制长期治疗的影响。利用干细胞通过它们秘密的蛋白质（即“分泌组”）的蛋白质的再生潜力代表了组织工程领域最近的范式转移。生物材料可用于本文雇用几种关键创新，包括使用定向进化来确定靶蛋白和材料之间的高特异性亲和力相互作用，以及使用生物传播建模来预测蛋白质亲和力相互作用和蛋白质分泌速率对整体蛋白质序列的影响，从而使蛋白质序列化对蛋白质序列化，从而启用了蛋白质材料的优化。这个高度的跨学科项目需要对生物工程，化学，生物学和人类生理学感兴趣的学员参与，并将吸引俄勒冈大学多个系的学生参与生物工程研究和教育。将开发一项包含在内的生物工程教育课程，以增加获得生物工程课程的访问权限，并为各种学科的学生提供专业和教学技能，以开发可持续的生物工程性外展活动，进而使用，这些活动可用于促进通过STEM中的K-12学生来促进生物启动的途径。智力优点和更广泛的影响审查标准。