Experimental Resources for Studies of Tenocyte Differentiation and Cell Fate Diversity

肌腱细胞分化和细胞命运多样性研究的实验资源

• 批准号: 9923524
• 负责人: RONEN SCHWEITZER
• 金额: $ 33.88万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923524
• 关键词: Address; Affect; Algorithms; Attention; Awareness; Basic Science; Biological Assay; Biological Process; Biology; Cell physiology; Cells; Clinic; Clinical; Communities; Cre driver; Data; Databases; Degenerative Disorder; Development; Effectiveness; Embryo; Financial Hardship; Funding Mechanisms; Gene Expression; Genes; Goals; Grant; In Situ Hybridization; Incidence; Individual; Information Resources; Investments; Leg; Ligaments; Morbidity - disease rate; Movement; Mus; Muscle; Muscle Contraction; Mutant Strains Mice; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Orthopedics; Outcome; Patients; Policies; Positioning Attribute; Public Health; Research; Research Project Grants; Resource Development; Resource Sharing; Resources; STEM program; Societies; Tendon Injuries; Tendon structure; Therapeutic Human Experimentation; Time; Tissues; Translational Research; Treatment Efficacy; United States National Institutes of Health; Visit; base; bone; cell type; chronic pain; clinical application; data resource; data sharing networks; follow-up; frontier; healing; improved; ligament injury; mouse model; progenitor; pup; regenerative; single-cell RNA sequencing; stem cells; success; symposium; tendon development; tool; transcriptome; transcriptome sequencing

Project Summary/Abstract Tendons connect muscles to bones and transmit the force generated by muscle contraction. Because of their unique position, the tendons are subject to significant shear and compression forces resulting in frequent tendon damage and tears. Tendons are also highly susceptive to development of degenerative conditions and because of slow and limited healing capacity tendon and ligament conditions account to more than 50% of visits to orthopedic clinics and present a major burden to individuals and society. A relative increase in tendon and ligament conditions in recent years led to a significant increase in the number of studies and research grants associated with tendons. This research is largely focused on clinical applications in tendons and it was recently recognized at NIAMS and within the research community that the basic research in tendons remained too limited and the absence of basic information resources is a major impediment to progress in tendon research. This understanding was indeed emphasized in the conclusions of a Tendon related conference sponsored by IAMS a few years ago. However, because of internal NIAMS policies, this realization was not followed by an RFA or NIH driven research consortium to address these experimental needs. Our labs has been at the forefront of identifying new tendon genes and developing research tools for tendon research in mouse and sharing them with the tendon community. We therefore decided to propose a project focused and the development of experimental resources and the rapid sharing of these resorces. The first aim in this project is therefore to use RNAseq in various developmental and mature stages and by comparison identify tendon differentiation stages and develop for each of these stages a comprehensive and authoritative list of genes with distinctive expression in tendons. In addition we will define a prorotypic short least of genes whose expression define these stages and can be used as success criteria for the programing of stem/progenitor cells to the tendon cell fate stages. In the second specific aim we will perform single cell RNAseq transcriptome assays to identify potential diversity of sub-specialized tenocytes in tendons. One cell type we will focus on in this aim is the epitenon, a critical part of the tendons that receives very limited research attention to date. Finally, the 3rd specific aim is to develop new mouse models for tendon research including additional cre lines with more specific targeted activity in tenocytes and associated cell types. And to develop additional mouse mutants to identify genes regulating the tendon cell fate. Since this project is defined as a resource development grant we will further focus on the rapid dissemination of all these data resources and mouse lines to support a more rapid progress in tendon and ligament research.

项目概要/摘要 肌腱将肌肉连接到骨骼并传递肌肉收缩产生的力。由于 由于其独特的位置，肌腱受到巨大的剪切力和压缩力，导致 频繁的肌腱损伤和撕裂。肌腱也非常容易发生退行性病变 由于肌腱和韧带状况缓慢且愈合能力有限， 超过 50% 的骨科诊所就诊人数，给个人和社会带来了重大负担。一个 近年来肌腱和韧带状况的相对改善导致了 与肌腱相关的研究和研究经费的数量。这项研究主要集中在 肌腱的临床应用，最近在 NIAMS 和研究中得到认可 社区认为肌腱的基础研究仍然太有限，缺乏基础研究 信息资源是肌腱研究进展的主要障碍。这种理解是 几年来 IAMS 主办的肌腱相关会议的结论中确实强调了这一点 前。然而，由于 NIAMS 内部政策的原因，RFA 或 NIH 并没有遵循这一认识 驱动研究联盟来满足这些实验需求。 我们的实验室一直处于识别新肌腱基因和开发研究工具的最前沿 小鼠肌腱研究并与肌腱社区分享。因此我们决定 提出项目重点并开发实验资源并快速共享 这些资源。因此，该项目的首要目标是在各种开发和研究中使用 RNAseq 成熟阶段并通过比较确定肌腱分化阶段并针对每个阶段进行发展 列出了在肌腱中具有独特表达的基因的全面且权威的列表。此外 我们将定义一个原型最短基因，其表达定义这些阶段并可用作 将干细胞/祖细胞编程至肌腱细胞命运阶段的成功标准。在第二个 具体目标是，我们将进行单细胞 RNAseq 转录组分析，以确定潜在的多样性 肌腱中的亚特化肌腱细胞。在这个目标中，我们将重点关注的一种细胞类型是表腱，它是一种关键的细胞类型。 迄今为止，研究关注度非常有限的肌腱的一部分。最后，第三个具体目标是 开发用于肌腱研究的新小鼠模型，包括具有更特异性的附加 cre 系 肌腱细胞和相关细胞类型的目标活性。并开发额外的小鼠突变体 识别调节肌腱细胞命运的基因。由于该项目被定义为资源开发 我们将进一步关注所有这些数据资源和鼠标线的快速传播 支持肌腱和韧带研究取得更快的进展。