Tendon TRAP: Targeted Therapeutic Delivery to Enhance Tendon Healing

Tendon TRAP：有针对性的治疗交付以增强肌腱愈合

• 批准号: 10612076
• 负责人: Danielle S. Benoit
• 金额: $ 20.33万
• 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: 2022-04-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10612076
• 关键词: Acute; Affinity; Animals; Area; Articular Range of Motion; Binding; Bone Resorption; Bone callus; Bone remodeling; Cell Lineage; Cells; Cicatrix; Data; Disease; Drug Delivery Systems; FOLH1 gene; Fibrosis; Fracture; Frequencies; Genes; Genetic; Genetic Transcription; Histologic; Histology; Home; Homing; Impairment; In Vitro; Inflammatory; Inflammatory Response; Injections; Injury; Kinetics; Knowledge; Label; Macrophage; Maleic Anhydride; Mechanics; Mediating; Mesenchymal; Modeling; Molecular; Molecular Profiling; Morphology; Mus; Myelogenous; Myeloid Cells; Natural regeneration; Operative Surgical Procedures; Osteoclasts; Outcome; Pathologic; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Population; Process; Recovery of Function; Reporter; Risk; S100A4 gene; Site; Styrenes; System; Tendon Injuries; Tendon structure; Testing; Therapeutic; Tissues; Translations; Work; bone fracture repair; cell type; comparison control; functional disability; functional improvement; functional restoration; healing; high reward; high risk; improved; in vivo; in vivo imaging; inhibitor; innovation; knock-down; leukemia; mechanical properties; mouse model; nanoparticle; nanoparticle delivery; nanoparticle drug; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; regenerative; repaired; response; small molecule; targeted treatment; tartrate-resistant acid phosphatase; therapeutic target; timeline; transcriptomic profiling; translational potential; uptake

Project Summary Following injury, tendons heal via a fibrotic scar-tissue response that impedes full functional restoration. Translation of pharmacotherapies to enhance tendon healing has been hampered by a combination of limited tendon targeting of systemic treatments, and insufficient identification of biologically informed therapeutic targets. In this high-risk high-reward study we will address both of these critical knowledge gaps. We have recently identified genetic knockdown of S100a4 as a novel model of functionally-enhanced tendon healing, thereby identifying S100a4 as a novel therapeutic target to improve tendon healing. Moreover, we have used spatial transcriptomic profiling to define the spatially distinct molecular processes that dictate the fibrotic tendon healing process. Using this approach we defined a macrophage-rich cluster located between the highly reactive tendon stubs at the injury site. This cluster was defined by enriched expression of Acp5, the gene encoding for TRAP (Tartrate resistant acid phosphatase). Our preliminary data further demonstrate regions of robust TRAP activity in the healing tendon. Here, we will capitalize on this exciting finding by leveraging our work using a TRAP binding peptide (TBP) conjugated nanoparticle (NP) drug delivery system. We have demonstrated enhanced homing and retention of TBP-NPs at sites of high TRAP activity including the bone fracture callus and during pathologic bone remodeling. Here, we will test the central hypothesis that TRAP binding peptide loaded nanoparticles (TBP-NPs) efficiently home to the healing tendon, are taken up by macrophages and that TBP-NP delivery of an S100a4 inhibitor enhances tendon regeneration compared to control TBP-NPs. In Aim 1 we will track the systemic and tendon-specific localization and retention of systemically administered fluorescently labelled TBP-NPs compared to scrambled control peptide-NPs. In addition, we will use a combination of cell-type specific fluorescent reporter mouse models to define the specific cell populations that uptake TBP-NPs during tendon healing. In Aim 2 we will define the loading and release profile of an S100a4 inhibitor on TBP-NPs and define the efficacy of TBP-NP drug delivery, compared to free drug and control NPs, to inhibit S100a4 expression and enhance the tendon healing process. Successful completion of these studies will establish a novel nanoparticle-mediate delivery system to target the healing tendon with high efficiency and efficacy, thereby substantially enhancing the translational feasibility of pharmacologically mediating improved tendon healing.

项目摘要 损伤后，肌腱通过纤维化瘢痕组织反应愈合，阻碍了完全功能恢复。 药物治疗促进肌腱愈合的转化受到限制， 全身性治疗的肌腱靶向，以及生物信息治疗的识别不足 目标的在这项高风险高回报的研究中，我们将解决这两个关键的知识差距。我们有 最近鉴定了S100 a4的基因敲除作为功能增强肌腱愈合的新模型， 从而将S100 a4鉴定为改善肌腱愈合的新的治疗靶点。此外，我们还使用 空间转录组学分析，以确定支配纤维化肌腱的空间上不同的分子过程 愈合过程使用这种方法，我们定义了一个富含巨噬细胞的集群，位于高度 损伤部位的反应性肌腱残端。该簇是通过基因Acp 5的富集表达来定义的 编码TRAP（抗酒石酸酸性磷酸酶）。我们的初步数据进一步表明， 在愈合的肌腱中具有强大的TRAP活性。在这里，我们将利用这一令人兴奋的发现， 使用TRAP结合肽（TBP）缀合的纳米颗粒（NP）药物递送系统工作。我们有 证明了TBP-NP在包括骨在内的高TRAP活性位点的增强的归巢和保留 骨折骨痂和病理性骨重建期间。在这里，我们将测试中心假设，即陷阱 结合肽负载的纳米颗粒（TBP-NPs）有效地回到愈合肌腱，被 与巨噬细胞相比，TBP-NP递送S100 a4抑制剂增强了肌腱再生。 对照TBP-NP。在目标1中，我们将跟踪系统和肌腱特异性定位和保留， 与乱序对照肽-NP相比，全身施用的荧光标记的TBP-NP。在 此外，我们将使用细胞类型特异性荧光报告小鼠模型的组合来定义 在肌腱愈合过程中摄取TBP-NP的特定细胞群。在目标2中，我们将定义负载， S100 a4抑制剂在TBP-NP上的释放曲线，并定义TBP-NP药物递送的功效，比较 游离药物和对照NP，抑制S100 a4表达并增强肌腱愈合过程。 这些研究的成功完成将建立一种新的纳米颗粒介导的传递系统，以靶向 以高效率和功效愈合肌腱，从而显著增强 促进肌腱愈合。