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 受伤后，肌腱通过纤维化疤痕传导反应愈合，阻碍了完全功能恢复。 有限的组合妨碍了药物治疗以增强肌腱愈合的药物疗法的翻译 肌腱靶向系统治疗，以及对生物学知情治疗的鉴定不足 目标。在这项高风险的高回报研究中，我们将解决这两个关键知识差距。我们有 最近将S100A4的遗传敲低确定为功能增强肌腱愈合的新模型， 从而将S100A4识别为改善肌腱愈合的新型治疗靶标。而且，我们已经使用了 空间转录组分析以定义决定纤维化肌腱的空间不同的分子过程 康复过程。使用这种方法，我们定义了一个位于高度巨噬细胞的集群 受伤部位的反应性肌腱存根。该簇是由ACP5的富集表达定义的，该基因是基因 编码陷阱（防strate抗性酸性磷酸酶）。我们的初步数据进一步证明了 愈合肌腱中强大的陷阱活性。在这里，我们将利用我们的发现来利用这一激动人心的发现 使用陷阱结合肽（TBP）共轭纳米颗粒（NP）药物输送系统进行工作。我们有 在高陷阱活性部位（包括骨骼）的位点显示了TBP-NP的归巢和保留 断裂愈伤组织和病理骨重塑期间。在这里，我们将测试陷阱的中心假设 结合肽载荷纳米颗粒（TBP-NP）有效地回到了愈合肌腱中 与 控制TBP-NP。在AIM 1中，我们将跟踪系统和肌腱特定的定位和保留 与加扰的对照肽-NP相比，系统地施用了荧光标记的TBP-NP。在 此外，我们还将结合细胞类型的特定荧光记者鼠标模型来定义 在肌腱愈合过程中摄取TBP-NP的特定细胞群体。在AIM 2中，我们将定义加载和 S100A4抑制剂在TBP-NP上的释放曲线，并定义了TBP-NP药物递送的功效 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个新型的纳米颗粒 - 中递送系统，以针对 具有高效率和功效的愈合肌腱，从而大大提高了翻译的可行性 药理介导的改善肌腱愈合。