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: 10852086
• 负责人: Anne E.C. Nichols
• 金额: $ 7.02万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10852086
• 关键词: Ablation; Administrative Supplement; Adrenal Cortex Hormones; Affect; American; Anti-Inflammatory Agents; Area; Award; Behavioral; Biological Markers; Biological Products; Biology; Biomechanics; Cell Differentiation process; Cells; Cellular biology; Clinic; Clinical; Data; Data Set; Dependence; Deposition; Exhibits; Future; Genes; Genetic; Goals; Hand Strength; Histologic; Histology; Immune; Inflammatory; Injury; Intervention; Knock-out; Knowledge; Measurement; Measures; Mediating; Methods; Modeling; Morphology; Mus; Musculoskeletal Diseases; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Opioid; Outcome Measure; Pain; Pain Research; Pain management; Parents; Pathology; Patients; Persistent pain; Pharmaceutical Preparations; Play; Population; Process; Property; Protease Inhibitor; Public Health; Quality of life; Rheumatism; Rodent; Role; Site; Tendon Injuries; Tendon structure; Testing; Time; Tissues; data reuse; design; efficacy testing; experimental study; functional outcomes; gait examination; healing; improved; innovation; insight; knock-down; mouse model; negative affect; novel; opioid use; pain inhibition; pressure; prevent; progenitor; recruit; response; secondary analysis; single-cell RNA sequencing; skin disorder; stem cells; therapeutic target; treatment effect

Project Summary Pain associated with tendon injuries is an difficult clinical problem that significantly affects the overall quality of life of affected patients. Current treatments for tendon pain are anti-inflammatory drugs (non-steroidal anti- inflammatory drugs (NSAIDS) and corticosteroids) or opioids; however, anti-inflammatory drugs can negatively affect the tendon healing process and long-term opioid use can lead to dependency and contributes to the national opioid public health crisis. Thus, the need for novel, more targeted mechanisms to alleviate pain in tendon injuries is high. The parent award seeks to define the overall role that epitenon cells play in tendon healing using a novel driver (GLASTCreERT) to track and manipulate epitenon cells (GLASTLin) through a combination of genetic lineage tracing, single-cell RNA-sequencing, and depletion/inhibitions studies. This administrative supplement builds on preliminary data gathered during completion of Aim 1 of the parent award wherein we discovered that a GLASTLin epitenon cells are the sole expressors of the peptidase inhibitor 16 (Pi16) gene, a key non-neuronal regulator of persistent pain. This suggests that Pi16 expression by epitenon cells may be a therapeutic target to mitigate the pain associated with tendon injury. Therefore, in parallel with the parent award, the proposed administrative supplement will test the central hypothesis that epitenon-derived cells are primary drivers of the tendon pain response. In supplemental experiments to Aim 2A of the parent award, we will first identify pain-related behavioral metrics that can be used to longitudinally evaluate tendon pain in mouse models. We will then assess how loss of Pi16 via GLASTLin epitenon cell depletion affects the pain response during healing by a combination of histological and pain-related behavioral analyses. Successful completion of these experiments will identify epitenon cell-derived Pi16 as a potential target by which tendon-related pain can be alleviated and establish methods to measure tendon pain in future studies.

项目摘要 与肌腱损伤相关的疼痛是一个困难的临床问题，其显著影响了手术的整体质量。 影响患者的生活。目前治疗肌腱疼痛的药物是抗炎药（非甾体抗炎药）， 抗炎药（NSAIDS）和皮质类固醇）或阿片类药物;然而，抗炎药可能 影响肌腱愈合过程，长期使用阿片类药物可导致依赖性， 国家阿片类药物公共卫生危机因此，需要新的，更有针对性的机制，以减轻疼痛， 肌腱损伤率很高。该奖项旨在确定肌腱外膜细胞在肌腱愈合中发挥的整体作用 使用新型驱动器（GLASTCreERT）通过以下组合来跟踪和操纵外膜细胞（GLASTLin）： 遗传谱系追踪、单细胞RNA测序和消耗/抑制研究。这一行政 补充建立在完成母奖项目标1期间收集的初步数据基础上， 发现GLASTLin外膜细胞是肽酶抑制剂16（Pi 16）基因的唯一表达者， 持续性疼痛的关键非神经调节因子。这表明，腱外膜细胞表达Pi 16可能是一种免疫调节剂。 治疗目标，以减轻与肌腱损伤相关的疼痛。因此，与母公司裁决同时， 拟议的行政补充将测试核心假设，即外膜衍生细胞是初级的， 肌腱疼痛反应的驱动因素。在对母公司奖励目标2A的补充实验中，我们将首先 识别疼痛相关的行为指标，可用于纵向评估小鼠模型中的肌腱疼痛。 然后，我们将评估通过GLASTLin外膜细胞耗竭导致的Pi 16缺失如何影响疼痛反应。 愈合的组织学和疼痛相关的行为分析的组合。成功完成这些 实验将确定腱外膜细胞衍生的Pi 16作为潜在的靶点，通过该靶点， 缓解和建立方法来衡量肌腱疼痛在未来的研究。