TIAM1 dictates lineage commitment in skeletal and soft tissue pericytes

TIAM1 决定骨骼和软组织周细胞的谱系承诺

• 批准号: 10350739
• 负责人: Ginny Ching-Yun Hsu
• 金额: $ 16.61万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-06 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350739
• 关键词: Adipocytes; Adipose tissue; Anabolism; Anatomy; Animals; Area; Arthritis; Award; Bioinformatics; Biological Assay; Biology; Biometry; Bone Regeneration; Bone Tissue; CRISPR/Cas technology; Calvaria; Cell Culture Techniques; Cell Differentiation process; Cell Therapy; Cells; Clinical; Clinical Trials; Clone Cells; Course Content; Data; Defect; Dental; Development; Development Plans; Educational workshop; Elements; Family; Fatty acid glycerol esters; Future; Gene Deletion; Genes; Goals; Histology; Human; Immunocompromised Host; Immunohistochemistry; Implant; In Vitro; Knock-out; Lead; Lymphoma; MCAM gene; Mentors; Mesenchymal; Mesenchymal Stem Cells; Minerals; Modeling; Molecular; Molecular Target; Monomeric GTP-Binding Proteins; Neoplasm Metastasis; Organ; Orthodontics; Pathway Analysis; Pathway interactions; Pericytes; Play; Population; Positioning Attribute; Postdoctoral Fellow; Predisposition; Property; Regenerative Medicine; Regulation; Reporter; Research; Research Personnel; Role; Science; Scientist; Signal Pathway; Source; TIAM1 gene; Techniques; Testing; Therapeutic; Thinking; Tissue Engineering; Tissues; Training; Translational Research; Universities; Work; Xenograft procedure; bone; bone cell; bone repair; career; career development; cartilage regeneration; cell preparation; clinically relevant; comparative; craniofacial; differential expression; human tissue; in vivo; inhibitor; interest; knowledgebase; medical schools; multidisciplinary; next generation sequencing; novel; osteogenic; overexpression; precursor cell; regeneration potential; research and development; rho; single-cell RNA sequencing; skeletal; skeletal tissue; skills; small molecule; soft tissue; stem cell biology; stem cell differentiation; stem cell fate; stem cells; tissue regeneration; tomography; transcriptome; transcriptomics; translational applications

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.

项目概要/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、 或支持组织导致无法愈合的骨缺损——这是骨科内外的一个重大临床问题。 被称为“间充质干细胞”（MSC）的混合基质群体具有明确的治疗作用。 对骨骼组织工程有好处，但最近使用 MSC 的临床试验表明效果不佳 或不一致的结果 我们的团队对用于组织工程的人类周细胞有着长期的兴趣。 然而，人类周细胞的组织特异性属性也日益得到认可。 研究人类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人 CD146+ 周细胞 结果显示 CD146+。 人类周细胞倾向于复制它们所源自的微环境（无论是骨环境还是骨环境）。 利用 FACS 纯化细胞的转录组分析。 克隆中，我们发现小 GTPase TIAM1 的 Rho 家族激活剂在细胞 在当前的 K08 提案中，我们将检验中心假设。 成骨抑制剂 TIAM1 维持人类周细胞的脂肪组织特性，并且该基因 缺失将驱动植入的人类周细胞中的骨合成代谢。 Ginny Ching-Yun Hsu 博士是约翰·霍普金斯大学医学院的博士后研究员， 接受过全面培训并长期致力于研究事业的正畸科学家。 职业发展计划使徐博士能够在三个领域获得额外的专业知识：1）干细胞和骨骼 生物学，2) 生物统计学和生物信息学，3) 转化研究将得到徐博士的支持。 优秀的多学科指导团队，其专业知识涵盖了她研究和职业生涯的所有要素 Aaron James 博士是血管周围干细胞、骨骼组织工程和发育方面的专家。 她的合作导师 Bruno Péault 博士是周细胞和转化研究领域的先驱。 她的共同导师 Patrick Cahan 博士和合作者 Linda Orzolek 女士将提供再生医学。 通过量身定制的课程，掌握下一代测序和生物信息学分析方面的专业知识， 研讨会和拟议的研究，徐博士将培养关键技能，以实现她成为一名 这项研究将成为骨生物学和组织工程领域成功的、独立的临床科学家。 为 R01 提案奠定基础，重点关注关节炎、骨和软骨中基于周细胞的细胞疗法 最后，该奖项将使徐医生成为一名顶级的正畸科学家，并使她能够 为口腔正畸领域做出重大贡献。