The Characterization of the Skeletogenic Stem Cells that Contribute to Post Natal Axial Skeletal Tissue Repair

有助于产后中轴骨骼组织修复的成骨干细胞的表征

• 批准号: 9109739
• 负责人: Beth Christie Bragdon
• 金额: $ 9.02万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-06 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109739
• 关键词: Applied Research; Basic Science; Biochemistry; Biological Process; Biology; Biophysics; Bone Marrow; Bone Marrow Stem Cell; Bone Matrix; Bone Regeneration; Bone Surface; Bone Tissue; Bone Transplantation; Bone callus; Boston; Burn Trauma; Cartilage; Cell Lineage; Cells; Clinical; Communication; Complement; Core Facility; Data; Defect; Development; Development Plans; Discipline; Engineering; Environment; Equilibrium; Event; FDA approved; Faculty; Fatty acid glycerol esters; Femur; Fluorescence-Activated Cell Sorting; Fracture; Fracture Healing; Genes; Goals; Healed; Heterotopic Ossification; Human; Impaired wound healing; Implant; In Vitro; Injury; Joints; Knowledge; Label; LacZ Genes; Lead; Leadership; Learning; Limb structure; Literature; Location; Marrow; Mentors; Mesenchymal Stem Cells; Microarray Analysis; Modeling; Molecular Biology; Morbidity - disease rate; Mus; Muscle; Natural regeneration; Operative Surgical Procedures; Orthopedic Surgery procedures; Osteogenesis; Pain; Periosteum; Population; Postdoctoral Fellow; Property; Publications; Recovery; Recruitment Activity; Reporter; Reporting; Research; Research Personnel; Resources; Running; Science; Scientist; Site; Skeleton; Smooth Muscle Actin Staining Method; Source; Stem cells; Surface; Tamoxifen; Technical Expertise; Testing; Therapeutic; Time; Tissues; Total Hip Replacement; Training; Transgenic Mice; Transgenic Organisms; Transplanted tissue; Trauma; Traumatic injury; Universities; Woman; base; bone; bone morphogenetic protein 2; career; career development; cost; craniofacial; differential expression; embryonic stem cell; experience; healing; implantation; improved; in vivo; interest; knowledge base; limb amputation; member; mouse model; multidisciplinary; osteogenic; prevent; progenitor; promoter; public health relevance; repaired; response; responsible research conduct; skeletal; skeletal tissue; skills; soft tissue; stem; stem cell differentiation; stem cell population; tissue repair; tissue trauma; transcription factor

 DESCRIPTION (provided by applicant): Candidate: Dr. Bragdon's training has been multidisciplinary encompassing biochemistry, molecular biology, and biophysics. During her research career she developed an interest in skeletal biology which she furthered by joining Dr. Gerstenfeld's lab and moving these interests into in vivo bone repair and regeneration models. Dr. Bragdon's long term goal is to become an independent researcher in an academic environment, pursuing basic and applied research in skeletal tissue biology to identify mechanisms that can be exploited as treatment for heterotrophic ossification, to advance current bone grafting materials, and to improve bone regeneration. In order to obtain these goals a career development plan has been developed by Drs. Gerstenfeld and Morgan, along with a co-mentor committee who will assist Dr. Bragdon as she transitions to an independent career. The mentor committee consists of both basic scientists and clinicians who will be able to provide clinical perspectives, interdisciplinary knowledge base, and independent advice. During this time additional research skills will be learned, specifically Fluorescence Activated Cell Sorting and microarray analysis. Equally balanced with learning of new technical skills will be professional development which is based on the National Postdoctoral Association Core Competencies and includes: communication, leadership and management, discipline-specific conceptual knowledge, professional skills, and responsible conduct of research. Resources available at Boston University will greatly aid in the career development of Dr. Bragdon. She will have access to core facilities run by faculty and staff members for technical advice, professional development through the Office of Professional development and Post-doctoral Affairs, BU Broadening Experiences in Scientific Training (BEST), Women in Science and Engineering, and Women in Networks. Research: Fractures are one of the most traumatic injuries that can occur in humans with 8 to 10 million fractures occurring annually which approximately 10% results in delayed or impaired healing. Repair is dependent upon the recruitment of mesenchymal stem cells (MSCs) to the injury site followed by a cascade of events resulting in the formation of cartilage and bone. A similar event can also occur in soft tissue due to trauma, burns, and total hip replacements resulting in boney tissue called ectopic or heterotopic ossification (HO). Multiple stem cell populations from the bone surface and muscle have been suggested to be involved however it is unclear as to the specific population of skeletogenic stem cells that are recruited or their location. Based on previous data the hypothesis of this proposal is that there i a "universal MSC" with in the axial limb tissues that contributes to injury induced bone formation. The aims of this proposal will 1) determine the stem cell contribution from the bone surface and muscle to the HO and identify whether the stem cell populations are similar, 2) determine the impact of muscle trauma has on the populations of recruited stem cells, and 3) determine the transcriptional machinery of these stem cell populations. In this proposal demineralized bone matrix will be implanted into inducible transgenic reporter mice models to induce ectopic bone formation. The mouse models will allow for the specific labeling and capturing of the different populations of cells known to induce during fracture and ectopic bone formation.

 描述（由申请人提供）：候选人：Bragdon博士的培训是多学科的，包括生物化学，分子生物学和生物物理学。在她的研究生涯中，她对骨骼生物学产生了兴趣，并加入了Gerstenfeld博士的实验室，将这些兴趣转移到体内骨修复和再生模型中。Bragdon博士的长期目标是成为学术环境中的独立研究人员，从事骨骼组织生物学的基础和应用研究，以确定可用于治疗异养骨化的机制，推进当前的骨移植材料，并改善骨再生。为了实现这些目标，Gerstenfeld博士和Morgan博士制定了职业发展计划，沿着的共同导师委员会将协助Bragdon博士过渡到独立职业。导师委员会由基础科学家和临床医生组成，他们将能够提供临床观点，跨学科知识基础和独立建议。在此期间，将学习其他研究技能，特别是荧光激活细胞分选和微阵列分析。与学习新的技术技能同样平衡的是基于国家博士后协会核心竞争力的专业发展，包括：沟通，领导和管理，特定学科的概念知识，专业技能和负责任的研究行为。波士顿大学提供的资源将大大有助于Bragdon博士的职业发展。她将有机会获得核心设施运行的教师和工作人员的技术咨询，通过专业发展和博士后事务办公室的专业发展，在科学培训（最好的），妇女在科学和工程，和妇女在网络拓展经验。研究：骨折是人类可能发生的最严重的创伤性损伤之一，每年发生800万至1000万例骨折，其中约10%导致愈合延迟或受损。修复依赖于间充质干细胞（MSC）向损伤部位的募集，随后是导致软骨和骨形成的级联事件。由于创伤、烧伤和全髋关节置换术，软组织也可能发生类似事件，导致称为异位或异位骨化（HO）的骨组织。来自骨表面和肌肉的多个干细胞群体已经被认为参与其中，但是尚不清楚招募的骨骼发生干细胞的特定群体或其位置。基于先前的数据，该提议的假设是在轴向肢体组织中存在有助于损伤诱导的骨形成的“通用MSC”。 本提案的目的是1）确定骨表面和肌肉对HO的干细胞贡献，并确定干细胞群是否相似，2）确定肌肉创伤对招募的干细胞群的影响，3）确定这些干细胞群的转录机制。在这个提议中，脱矿骨基质将被植入到可诱导的转基因报告小鼠模型中以诱导异位骨形成。小鼠模型将允许特异性标记和捕获已知在骨折和异位骨形成期间诱导的不同细胞群。