CAREER: Modeling Stem Cell Decision-Making During Vascularized Bone Development

职业：在血管化骨发育过程中模拟干细胞决策

• 批准号: 1350554
• 负责人: Warren Grayson
• 金额: $ 40万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1350554&HistoricalAwards=false
• 关键词: CAREER; Modeling; Stem; Cell; Decision

1350554 Grayson, Warren L.The supply of vascularized bone grafts for the therapeutic regeneration of large, non-healing bone defects remains a huge unmet clinical need affecting more than one million people in the US every year. Tissue engineering solutions have the potential to significantly advance currently available treatment methods. The data from this study will be utilized to significantly improve approaches to engineer functional vascularized bone grafts for regenerative medicine. Results from this CAREER project will be integrated into the educational curricula taught by the PI, providing students with the tools needed to perform cutting-edge research and improve fundamental understanding of cell and developmental biology as it pertains to tissue engineering. The educational benefit will be extended to international students who will be exposed to world-class research environments through intensive summer internships. The award will also benefit 'at-risk' minority high school students through the establishment of a transformative internship program.The overall objective of this CAREER proposal is to develop a fundamental understanding of how the decision of stem cells to commit to a particular lineage during tissue formation impacts the structure and morphology of engineered tissue constructs. During vascularized bone formation in cell culture models, mesenchymal stem cells differentiate into pericytes (to stabilize the nascent vasculature) and osteoblasts (to deposit mineral). This decision to become pericyte or osteoblasts varies as a function of both space and time in culture. Both cell types are critical for the formation and maintenance of the appropriate tissue organization yet it remains unclear how the perivascular microenvironment impacts the lineage specification of stem cells into either of these particular phenotypes. By combining tissue engineering cell-culture models with molecular biology techniques it is possible to explore the intricate cell-fate decisions that regulate complex tissue formation. This proposal tests the hypothesis that regulating the pericyte/osteoblast lineage commitment of mesenchymal stem cells as a function of space (proximity to vascular structures) and time underlies the potential to form integrated vascular networks and mineralized bone deposits. There are three primary research objectives: (i) Determine the effect of cell composition and growth factor delivery on the structure and organization of tissue engineered vascularized bone. (ii) Evaluate effect of growth factor concentration and spatial gradients on tissue structure. (iii) Investigate the role of pericyte and osteoblast plasticity in mediating vascularized bone development.This CAREER award by the Biotechnology, Biochemical, and Biomass Engineering Program of the CBET Division is co-funded by the Biomaterials Program of the Division of Materials Research and by the Mathematical Biology Program of the Division of Mathematical Sciences.

1350554 Grayson，Warren L.供应血管化骨移植物用于治疗性再生大的、不愈合的骨缺损仍然是一个巨大的未满足的临床需求，每年影响美国100多万人。组织工程解决方案有可能显着推进目前可用的治疗方法。这项研究的数据将被用来显着改善方法，工程师的功能血管化骨移植再生医学。该CAREER项目的结果将被整合到PI教授的教育课程中，为学生提供进行尖端研究所需的工具，并提高对细胞和发育生物学的基本理解，因为它涉及组织工程。教育效益将扩大到国际学生谁将通过密集的暑期实习接触到世界一流的研究环境。该奖项还将通过建立一个变革性的实习计划，使“有风险”的少数民族高中生受益。该CAREER提案的总体目标是从根本上了解干细胞在组织形成过程中承诺特定谱系的决定如何影响工程组织构建物的结构和形态。在细胞培养模型中血管化骨形成期间，间充质干细胞分化成周细胞（以稳定新生血管系统）和成骨细胞（以存款矿物质）。这种决定成为周细胞或成骨细胞的变化作为一个功能的空间和时间的文化。这两种细胞类型对于形成和维持适当的组织结构都是至关重要的，但目前仍不清楚血管周围微环境如何影响干细胞的谱系特化为这些特定表型中的任一种。通过将组织工程细胞培养模型与分子生物学技术相结合，有可能探索调节复杂组织形成的复杂细胞命运决定。该提案测试了以下假设：调节间充质干细胞的周细胞/成骨细胞谱系定型作为空间（接近血管结构）和时间的函数，是形成整合的血管网络和矿化骨沉积的潜力的基础。主要研究目标有三：（i）确定细胞组成和生长因子递送对组织工程化血管化骨的结构和组织的影响。(ii)评价生长因子浓度和空间梯度对组织结构的影响。(iii)研究周细胞和成骨细胞可塑性在调节血管化骨发育中的作用。CBET部生物技术、生物化学和生物质工程项目的CAREER奖由材料研究部生物材料项目和数学科学部数学生物学项目共同资助。