TIAM1 dictates lineage commitment in skeletal and soft tissue pericytes

项目摘要/摘要 骨组织具有很高的内在再生潜力，但间充质前体数量、功能、 或支持性组织导致无法愈合的骨缺损-这是一个重大的临床问题 牙科。被称为“间充质干细胞”(MSCs)的混合基质细胞有明确的治疗作用 骨组织工程的益处，然而，最近使用MSC的临床试验表明，MSC的效果不佳 或者结果不一致。我们的团队长期以来一直对用于组织工程的人周细胞感兴趣。 然而，人类周细胞的组织特异性属性也得到了越来越多的认识。为了进一步 研究人周细胞的组织特异性特性，我们最近检查了FACS的差异 从骨骼或软组织来源纯化的人CD146周细胞。结果表明，CD146 人类周细胞有复制其来源的微环境的趋势(无论是骨还是骨)。 形成或脂肪形成取决于起源的组织)。利用FACS纯化细胞的转录分析 克隆，我们发现Rho家族的小GTP酶激活因子TIAM1在细胞内起着关键作用 人类周细胞的分化决定。在当前的K08提案中，我们将检验中心假设 成骨抑制物TIAM1维持人类周细胞的脂肪组织特性，以及该基因 缺失将促使植入的人周细胞之间的骨合成代谢。 约翰霍普金斯大学医学院博士后徐静云博士是一位 正畸医生--受过全面训练并长期致力于研究事业的科学家。这个 职业发展计划使许博士在三个领域获得了更多的专业知识：1)干细胞和骨骼 生物学，2)生物统计学和生物信息学，3)翻译研究。许博士将由一名 优秀的多学科指导团队，具备涵盖其研究和职业生涯所有要素的专业知识 发展。艾伦·詹姆斯博士，血管周围干细胞、骨骼组织工程和 翻译研究是她的主要导师。她的共同导师布鲁诺·佩尔特博士是周细胞和 再生医学。她的合作导师Patrick Cahan博士和合作者Linda Orzolek女士将提供 在下一代测序和生物信息学分析方面的专业知识。通过量身定制的课程设置， 研讨会和拟议的研究，徐博士将发展关键技能，以实现她成为一名 在骨生物学和组织工程领域成功、独立的临床医生和科学家。这项研究将 为R01提案奠定基础，专注于关节炎、骨骼和软骨的基于周细胞的细胞治疗 再生。最后，这个奖项将使许医生成为一名顶级的正畸科学家，并使她 为正畸领域做出重大贡献。

Project Summary/Abstract Bone tissue has high intrinsic regenerative potential, yet deficits in mesenchymal precursor numbers, function, or supportive tissues lead to non-healing bony defects – a significant clinical problem within and outside of the dental sciences. Mixed stromal populations termed `mesenchymal stem cells' (MSCs) have clear therapeutic benefit for skeletal tissue engineering, however recent clinical trials using MSC have demonstrated suboptimal or inconsistent results. Our team has a long-standing interest in human pericytes for tissue engineering. However, the tissue-specific attributes of human pericytes has also been increasingly recognized. To further investigate the tissue-specific properties of human pericytes, we recently examined differences in FACS purified human CD146+ pericytes from either skeletal or soft tissue sources. Results showed that CD146+ human pericytes have a tendency to replicate the microenvironment from which they are derived (either bone- forming or fat-forming depending on tissue of origin). Leveraging transcriptomic analysis of FACS-purified cell clones, we found that the activator of the Rho family of small GTPases TIAM1 plays a critical role in cellular differentiation decisions in human pericytes. In the current K08 proposal, we will test the central hypothesis that the osteogenic inhibitor TIAM1 maintains the adipose tissue identity of human pericytes, and that gene deletion will drive bone anabolism among implanted human pericytes. Dr. Ginny Ching-Yun Hsu, a postdoctoral fellow at the Johns Hopkins University School of Medicine, is an orthodontist-scientist with a well-rounded training and a long-standing commitment to a research career. The career development plan enables Dr. Hsu to gain additional expertise in three areas: 1) stem cell and bone biology, 2) biostatistics and bioinformatics, and 3) translational research. Dr. Hsu will be supported by an outstanding multidisciplinary mentoring team with expertise to cover all elements of her research and career development. Dr. Aaron James, an expert in perivascular stem cells, skeletal tissue engineering and translational research, is her primary mentor. Her co-mentor Dr. Bruno Péault is a pioneer in pericytes and regenerative medicine. Her co-mentor Dr. Patrick Cahan and collaborator Ms. Linda Orzolek will provide expertise in next-generation sequencing and bioinformatics analyses. Through a tailored curriculum of courses, workshops, and the proposed research, Dr. Hsu will develop crucial skills to achieve her goal of becoming a successful, independent clinician-scientist in the field of bone biology and tissue engineering. This research will generate the basis for R01 proposals, focusing on pericyte-based cell therapy in arthritis, bone and cartilage regeneration. Finally, this award will position Dr. Hsu to become a top-tier orthodontist-scientist and enable her to make a significant contribution to the field of orthodontics.