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.

项目总结/摘要 骨组织具有高的内在再生潜力，但缺乏间充质前体数量、功能， 或支持组织导致不愈合的骨缺损，这是骨缺损内外的一个重要临床问题。 牙科科学称为“间充质干细胞”（MSC）的混合基质群具有明确的治疗作用。 然而，最近使用MSC的临床试验表明， 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越来越被认识到。进一步 为了研究人类周细胞的组织特异性，我们最近研究了流式细胞仪的差异， 来自骨骼或软组织来源的纯化的人CD 146+周细胞。结果显示，CD 146 + 人周细胞具有复制它们所来源的微环境（骨， 形成或形成脂肪，这取决于组织来源）。利用FACS纯化的细胞的转录组学分析 克隆，我们发现小GTP酶的Rho家族的激活剂TIAM 1在细胞凋亡中起关键作用。 在人周细胞中的分化决定。在当前的K 08提案中，我们将检验中心假设 成骨抑制剂TIAM 1维持了人类周细胞的脂肪组织特性， 缺失将在植入的人周细胞中驱动骨愈合。 博士约翰霍普金斯大学医学院的博士后研究员Ginny Ching-Yun Hsu是一位 具有全面培训和长期致力于研究事业的非营利科学家。的 职业发展计划使徐博士在三个领域获得额外的专业知识：1）干细胞和骨 生物学，2）生物统计学和生物信息学，以及3）转化研究。徐博士将得到一位 优秀的多学科指导团队，拥有涵盖其研究和职业生涯所有要素的专业知识 发展亚伦·詹姆斯博士是血管周围干细胞、骨骼组织工程和 翻译研究是她的主要导师她的共同导师Bruno Péault博士是周细胞研究的先驱， 再生医学她的共同导师帕特里克卡汉博士和合作者琳达Orzolek女士将提供 下一代测序和生物信息学分析的专业知识。通过量身定制的课程设置， 研讨会，以及拟议的研究，徐博士将发展关键技能，以实现她的目标，成为一个 骨生物学和组织工程领域的成功、独立的临床科学家。这项研究将 为R 01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 再生最后，这个奖项将定位徐博士成为一个顶级的生物科学家，使她能够 对数学领域做出了重大贡献。