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; 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.

项目摘要 这项K99/R00 NIH独立奖申请申请概述了研究培训和职业 开发计划将为安妮·尼科尔斯博士做好准备，成为职业生涯 肌腱细胞机制。该研究项目旨在培训尼科尔斯博士使用尖端 转录组分析和深入的机械测试技术，以回答有关有关的基本问题 Epitenon的作用，这是一个围绕所有肌腱的结构较差的作用。虽然想为许多人服务 重要的功能，由于缺乏通用，epitenon的真实身份和功能仍然难以捉摸 专门针对上皮细胞的标记。在初步研究中，尼科尔斯博士确定了一种新颖的异源， epitenon中的glast-linege（glastlin）细胞的种群有助于两种肌腱愈合之后 通过区分硬化性（SCX） - 表达宁静。鉴定遗传标志物的表位细胞及其证明 延伸性差异化的能力为肌腱研究开辟了新的新途径，这将形成 尼科尔斯博士独立研究计划的基础。本提案中概述的目的将基于这些 初步研究并利用Dr. Dr.开发的众多复杂的遗传小鼠模型 Nichols测试了中心假设，即Glastlin Epitenon细胞是必不可少的终止来源 尾子愈合和适应的祖细胞。在该奖项的K99阶段，她将定义 各种格拉斯特林体皮亚群，并确定用作延期祖先的特定子集 池（AIM 1），并证明适当的肌腱愈合需要Glastlin Epitenon细胞（AIM 2）。期间 R00阶段Nichols博士将在Glastlin Epitenon细胞和Tenocytes之间建立协调一致作为钥匙 适应性肌腱生长的效应因子（AIM 3）。总的来说，这些数据将提供第一个综合 表征上皮细胞及其在肌腱生物学中的功能。除了严格的科学培训 计划，URMC的职业发展活动，例如授予写作研讨会，实验室精神和教学 在K99阶段的经验将使尼科尔斯博士在R00阶段过渡到教师职位。博士 尼科尔斯还将从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）。除了遗传小鼠 她的主要心理Alayna Loiselle博士的模型和空间RNA的专业知识与她的互动 SMCDAC将允许Nichols博士获得单细胞转录组分析的其他专业知识（Chia-博士 肺WU），机械测试技术（Mark Buckley博士）和肌腱适应模型（Lou博士 Soslowsky）。在她的SMCDAC职业顾问的帮助和重要反馈下（Soslowsky博士，Laura Calvi， 和罗伯特·迪克森（Robert Dirksen）），尼科尔斯博士将为成功竞争教师职位并领导她 自己的独立研究计划。