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.

干细胞具有修复损伤和病变组织的潜力，因此在再生医学领域有着巨大的前景。然而，干细胞的前景尚未完全实现，因为大多数在损伤后移植到体内的干细胞在移植后迅速死亡。尽管它们的命运，这些干细胞仍然经常设法对它们移植到其中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，这可以减少炎症并使环境更适合宿主细胞的浸润以再生受损组织。然而，蛋白质通常也不会长时间保留在损伤部位，使其效果短暂。该CAREER提案的目标是开发生物材料来捕获和浓缩这些有效的细胞分泌蛋白，以增强和延长其治疗效果，使其超过干细胞存活的初始期。这些生物材料将被工程化以仅从细胞分泌蛋白质的复杂混合物中捕获特定的感兴趣蛋白质，从而允许它们充当筛富集治疗蛋白质而不捕获无效蛋白质。对于广泛的社会影响，从复杂混合物中选择性富集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，包括肌肉骨骼损伤，心血管疾病和脊髓损伤具有重要意义。这个高度跨学科的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，并将使俄勒冈州大学多个部门的学生参与生物工程研究和教育。将开发一个包容性的生物工程教育课程，为来自不同学科的学生提供必要的技能，以开发可持续的生物工程推广活动，这些活动反过来可以用于促进K-12学生在科学，技术，工程和数学（STEM）方面代表性不足的生物工程途径。通过增加获得生物工程课程在多个层次（K-12，本科生和研究生），拟议的工作将多样化的人才库的科学家和工程师的技能和愿望，从事跨学科的生物工程research.Technical Abstract间充质干/基质细胞（MSC）分泌的蛋白质，可以介导的免疫反应损伤和刺激组织修复。然而，移植的MSC的存活率差可能限制长期治疗效果。通过干细胞分泌的蛋白质（即，“分泌蛋白质组”）代表了组织工程领域中最近的范式转变。生物材料可用于隔离并延长分泌蛋白的呈递，使其超过细胞存活的初始期。然而，目前的生物材料从复杂的蛋白质混合物中选择性地螯合特定靶蛋白的能力有限。这个CAREER提案的目标是开发一个基于亲和力的生物材料库，可以选择性地隔离和呈递MSC分泌的治疗蛋白。本文将采用几个关键的创新，包括使用定向进化来鉴定靶蛋白和材料之间的高特异性亲和力相互作用，以及使用生物运输建模来预测蛋白质-材料亲和力相互作用和蛋白质分泌速率对整体蛋白质螯合的影响，从而能够优化用于蛋白质螯合的生物材料。这个高度跨学科的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，并将使俄勒冈州大学多个部门的学生参与生物工程研究和教育。将开发一个包容性的生物工程教育课程，以增加获得生物工程课程的机会，并为来自不同学科的学生提供专业和教学技能，以开展可持续的生物工程外联活动，用于促进生物工程的途径，该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识产权评估来支持。优点和更广泛的影响审查标准。