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: 10604400
• 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/10604400
• 关键词: Adipocytes; Adipose tissue; Anabolism; Anatomy; Animals; Area; Arthritis; Award; Bioinformatics; Biological Assay; Biology; Biometry; Blood Vessels; Bone Regeneration; Bone Tissue; CRISPR/Cas technology; Calvaria; Cell Culture Techniques; Cell Differentiation process; Cell Therapy; Cells; Clinical; Clinical Trials; Clone Cells; Course Content; Cytoskeleton; 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; MCAM gene; Mentors; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Monomeric GTP-Binding Proteins; Organ; Orthodontics; Pathway Analysis; Pathway interactions; Pericytes; Physiologic Ossification; 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; mineralization; 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; transdifferentiation; translational applications; Adipocytes; Adipose tissue; Anabolism; Anatomy; Animals; Area; Arthritis; Award; Bioinformatics; Biological Assay; Biology; Biometry; Blood Vessels; Bone Regeneration; Bone Tissue; CRISPR/Cas technology; Calvaria; Cell Culture Techniques; Cell Differentiation process; Cell Therapy; Cells; Clinical; Clinical Trials; Clone Cells; Course Content; Cytoskeleton; 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; MCAM gene; Mentors; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Monomeric GTP-Binding Proteins; Organ; Orthodontics; Pathway Analysis; Pathway interactions; Pericytes; Physiologic Ossification; 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; mineralization; 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; transdifferentiation; 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.

项目摘要/摘要 骨组织具有较高的内在再生潜力，但在间充质前体数量，功能， 或支持的时机导致非修订奖励缺陷 - 在此内和外部的一个重大临床问题 牙科科学。称为“间充质干细胞”（MSC）的混合基质种群具有明确的治疗 对骨骼组织工程的好处，但是最近使用MSC的临床试验表现出了次优的 或结果不一致。我们的团队对人类周期对组织工程有长期的兴趣。 但是，人周细胞的组织特异性属性也越来越多地被识别。进一步 研究人周细胞的组织特异性特异性，我们最近检查了FAC的差异 来自骨骼或软组织源的纯化的人CD146+周细胞。结果表明CD146+ 人周细胞具有复制其得出的微环境的趋势（要么 根据原点组织形成或形成脂肪）。利用FACS纯化细胞的转录组分析 克隆，我们发现小gtpases的Rho家族TIAM1的活化剂在细胞中起着至关重要的作用 人周细胞中的分化决策。在当前的K08提案中，我们将检验中心假设 成骨抑制剂TIAM1保持人周细胞的脂肪组织身份，该基因 删除将驱动植入的人周细胞中的骨变质化。 约翰·霍普金斯大学医学院的博士后研究员金妮·钦（Ginny Ching-Yun Hsu）博士是 牙齿矫正医生进行了全面的培训和对研究职业的长期承诺。 职业发展计划使HSU博士能够在三个领域获得更多专业知识：1）干细胞和骨头 生物学，2）生物统计学和生物信息学，以及3）转化研究。 HSU博士将得到 杰出的多学科指导团队具有专业知识，以涵盖其研究和职业的所有要素 发展。 Aaron James博士，血管血管干细胞的专家，骨骼组织工程和 翻译研究是她的主要导师。她的联合官员布鲁诺·佩特（BrunoPéault）博士是周细胞的先驱， 她的联合官员帕特里克·卡汉（Patrick Cahan）和合作者琳达·奥佐尔（Linda Orzolek）将提供 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， 研讨会以及拟议的研究，HSU博士将发展至关重要的技能，以实现她成为一个的目标 成功的独立临床科学家在骨生物学和组织工程领域。这项研究会 生成R01提案的基础，重点是基于周细胞的细胞治疗关节炎，骨骼和软骨 再生。最后，该奖项将使HSU博士成为顶级牙齿矫正医生，并使她启用她 为正畸领域做出重大贡献。