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，它显着影响 受影响患者的生活。肌腱疼痛的当前治疗方法是抗炎药（非甾体抗炎药 炎症药（NSAIDS）和皮质类固醇）或阿片类药物；但是，抗炎药可能会负面 影响肌腱愈合过程和长期阿片类药物的使用可能导致依赖性，并有助于 国家阿片类药物公共卫生危机。因此，需要新颖，更具针对性的机制来减轻疼痛 肌腱受伤很高。父母奖旨在定义肠细胞在肌腱愈合中扮演的整体角色 使用新型驱动器（GlastCreert）通过组合结合 遗传谱系追踪，单细胞RNA测序和耗竭/抑制作用。这个行政 补充基于在父母奖的AIM 1完成期间收集的初步数据，我们在其中 发现glastlin表位细胞是肽酶抑制剂16（pi16）基因的唯一表达式，A 持续性疼痛的关键非神经调节剂。这表明表位细胞的PI16表达可能是一个 治疗靶标可减轻与肌腱损伤相关的疼痛。因此，与父母奖并行 拟议的行政补充剂将检验中心假设，即上皮源性细胞是主要的 肌腱疼痛反应的驱动器。在接受父母奖的AIM 2A的补充实验中，我们将首先 确定可用于纵向评估小鼠模型中肌腱疼痛的行为指标。 然后，我们将通过Glastlin Epitenon细胞耗竭来评估PI16的损失如何影响疼痛反应 通过组织学和疼痛相关的行为分析的结合来治愈。这些成功完成 实验将识别出上皮细胞衍生的PI16是一个潜在的靶标，可以通过肌腱相关的疼痛 在未来的研究中缓解并建立了测量肌腱疼痛的方法。