Epitenon-derived progenitor cells in tendon healing and adaptation

表腱衍生的祖细胞在肌腱愈合和适应中的作用

• 批准号: 10640168
• 负责人: Anne E.C. Nichols
• 金额: $ 10.62万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-07 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640168
• 关键词: Ablation; Acute; Advisory Committees; Affect; American; Atlases; Award; Biological Products; Biology; Biomechanics; Bone remodeling; Cell Differentiation process; Cell Lineage; Cells; Communication; Data; Deposition; Development Plans; Educational process of instructing; Educational workshop; Faculty; Feedback; Flexor; Foundations; Future; GLAST Protein; Genes; Genetic; Genetic Markers; Goals; Grant; Growth; Homeostasis; Injury; Knowledge; Lead; Lung; Mechanics; Mentors; Mentorship; Modeling; Molecular; Morphology; Musculoskeletal; Osteoblasts; Osteocytes; Pathology; Pathway Analysis; Pathway interactions; Periosteum; Phase; Physiological; Population; Positioning Attribute; Process; Property; Quality of life; Research; Research Personnel; Research Project Grants; Research Training; Role; Source; Structure; Techniques; Tendon Injuries; Tendon structure; Testing; Tissues; Training; United States National Institutes of Health; Work; Writing; biomechanical test; bone; career; career development; cell type; design; experience; experimental study; gene regulatory network; genetic signature; healing; imaging study; improved; insight; interest; mechanical load; mouse model; novel; osteoblast differentiation; physiologic model; postnatal; prevent; progenitor; programs; repaired; response; scleraxis; single-cell RNA sequencing; stem cells; tendon development; transcription factor; transcriptome sequencing; transcriptomics

Project Summary This K99/R00 NIH Pathway to Independence Award application outlines the research training and career development plan that will prepare Dr. Anne Nichols for a career as an independent investigator in the field of tendon cell mechanobiology. The research project is designed to train Dr. Nichols in the use of cutting-edge transcriptomic analyses and in-depth mechanical testing techniques to answer fundamental questions about the role of the epitenon, a poorly characterized structure surrounding all tendons. Though thought to serve many important functions, the true identity and function of the epitenon has remained elusive due to a lack of genetic markers that specifically target epitenon cells. In preliminary studies, Dr. Nichols identified a novel, heterogenous, population of GLAST-lineage (GLASTLin) cells in the epitenon that contribute to both tendon healing following acute injury and tendon adaptation in response to mechanical overload by differentiating into scleraxis (Scx)- expressing tenocytes. Identification of a genetic marker for epitenon cells as well as demonstration of their capacity for tenogenic differentiation has opened an exciting new avenue of tendon research that will form the basis of Dr. Nichols’ independent research program. The aims outlined in this proposal will build on these preliminary studies and make use of the numerous sophisticated genetic mouse models developed by Dr. Nichols to test the central hypothesis that GLASTLin epitenon cells are an indispensable source of tenogenic progenitor cells for both tendon healing and adaptation. During the K99 phase of this award, she will define the various GLASTLin epitenon subpopulations and identify the specific subset that serves as a tenogenic progenitor pool (Aim 1) and demonstrate that GLASTLin epitenon cells are required for proper tendon healing (Aim 2). During the R00 phase, Dr. Nichols will establish coordination between GLASTLin epitenon cells and tenocytes as a key effector of adaptive tendon growth (Aim 3). Collectively, these data will provide the first comprehensive characterization of epitenon cells and their function in tendon biology. In addition to a rigorous scientific training plan, career development activities at URMC, such as grant-writing workshops, lab mentorship, and teaching experience during the K99 phase will prepare Dr. Nichols to transition to a faculty position in the R00 phase. Dr. Nichols also will benefit greatly from the collective scientific expertise and career advice of her assembled Scientific Mentoring and Career Development Advisory Committee (SMCDAC). In addition to the genetic mouse model and spatial RNA-sequencing expertise of her primary mentor, Dr. Alayna Loiselle, interaction with her SMCDAC will allow Dr. Nichols to acquire additional expertise in single-cell transcriptomic analyses (Dr. Chia- Lung Wu), mechanical testing techniques (Dr. Mark Buckley), and models of tendon adaptation (Dr. Lou Soslowsky). With the help and critical feedback of her SMCDAC career advisors (Drs. Soslowsky, Laura Calvi, and Robert Dirksen), Dr. Nichols will be well-prepared to successfully compete for faculty positions and lead her own independent research program.

项目概要 此 K99/R00 NIH 独立之路奖申请概述了研究培训和职业 发展计划，将使安妮·尼科尔斯博士为该领域的独立调查员的职业生涯做好准备 该研究项目旨在培训尼科尔斯博士使用尖端技术。 转录组分析和深入的机械测试技术来回答有关 腱腱的作用，一种围绕所有肌腱的特征明确的结构，被认为可以为许多人服务。 由于缺乏遗传信息，表腱的真实身份和功能仍然难以捉摸。 在初步研究中，尼科尔斯博士发现了一种新的异质标记物。 腱膜上的 GLAST 谱系 (GLASTLin) 细胞群有助于肌腱愈合 通过分化为巩膜（Scx）来应对机械过载的急性损伤和肌腱适应 表达肌腱细胞的遗传标记的鉴定及其证明。 肌腱分化的能力为肌腱研究开辟了一条令人兴奋的新途径，它将形成 尼科尔斯博士的独立研究计划的基础，该提案中概述的目标将建立在这些基础上。 初步研究并利用了 Dr. 开发的众多复杂的基因小鼠模型。 Nichols 检验了 GLASTLin 表腱细胞是腱发生不可或缺的来源这一中心假设 在该奖项的 K99 阶段，她将定义肌腱愈合和适应的祖细胞。 各种 GLASTLin epitenon 亚群，并鉴定作为腱祖细胞的特定亚群 池（目标 1）并证明 GLASTLin 表腱细胞是肌腱正常愈合所必需的（目标 2）。 R00阶段，Nichols博士将建立GLASTLin表腱细胞和肌腱细胞之间的协调作为关键 总的来说，这些数据将提供第一个全面的肌腱生长效应。 除了严格的科学训练外，还了解表腱细胞的特征及其在肌腱生物学中的功能。 计划、URMC 的职业发展活动，例如资助写作研讨会、实验室指导和教学 K99 阶段的经验将为 Nichols 博士过渡到 R00 阶段的教员职位做好准备。 尼科尔斯也将从她聚集的集体科学专业知识和职业建议中受益匪浅。 科学指导和职业发展咨询委员会（SMCDAC） 除了基因小鼠。 她的主要导师 Alayna Loiselle 博士的模型和空间 RNA 测序专业知识与她的互动 SMCDAC 将使 Nichols 博士获得单细胞转录组分析方面的额外专业知识（Chia- Lung Wu）、机械测试技术（Mark Buckley 博士）和肌腱适应模型（Lou 博士） 在她的 SMCDAC 职业顾问（Soslowsky 博士、Laura Calvi 博士）的帮助和批评性反馈下， 和罗伯特·德克森），尼科尔斯博士将做好充分准备，成功竞争教职并领导她 自己的独立研究计划。