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.

项目概要 受伤后，肌腱通过纤维化疤痕组织反应愈合，从而阻碍功能的全面恢复。 促进肌腱愈合的药物疗法的转化受到有限的组合的阻碍 全身治疗的肌腱靶向，以及生物学信息治疗的识别不足 目标。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 最近发现 S100a4 的基因敲除是一种功能增强肌腱愈合的新模型， 从而确定 S100a4 作为改善肌腱愈合的新治疗靶点。此外，我们还使用了 空间转录组分析来定义决定纤维化肌腱的空间不同分子过程 愈合过程。使用这种方法，我们定义了一个富含巨噬细胞的簇，位于高度 受伤部位的反应性肌腱残端。该簇是由 Acp5（基因）的富集表达定义的 TRAP（抗酒石酸酸性磷酸酶）的编码。我们的初步数据进一步表明 愈合肌腱中强大的 TRAP 活性。在这里，我们将利用我们的技术来利用这一令人兴奋的发现 使用 TRAP 结合肽 (TBP) 缀合纳米颗粒 (NP) 药物输送系统进行工作。我们有 证明 TBP-NP 在高 TRAP 活性位点（包括骨）的归巢和保留增强 骨折愈伤组织和病理性骨重建过程中。在这里，我们将检验中心假设 TRAP 结合肽负载纳米颗粒（TBP-NP）有效地定位于愈合肌腱，被 与巨噬细胞相比，S100a4 抑制剂的 TBP-NP 递送可增强肌腱再生 控制 TBP-NP。在目标 1 中，我们将跟踪系统性和肌腱特异性的定位和保留 与乱序对照肽-NP 相比，全身施用荧光标记的 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，我们将定义加载和 S100a4 抑制剂在 TBP-NP 上的释放曲线并确定 TBP-NP 药物递送的功效，比较 释放药物和控制 NP，抑制 S100a4 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型纳米颗粒介导的递送系统，以靶向 高效、有效地愈合肌腱，从而大大提高了转化的可行性 药物介导改善肌腱愈合。