Functional role and therapeutic potential of hedgehog signaling in tendon-to-bone repair

刺猬信号在腱骨修复中的功能作用和治疗潜力

• 批准号: 10431935
• 负责人: Nathaniel A. Dyment
• 金额: $ 34.09万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10431935
• 关键词: Address; Adult; Agonist; Anterior; Automobile Driving; Biological Assay; Biology; Biomechanics; Bone Marrow; Cell Differentiation process; Cells; Clinical; Clinical Treatment; Collagen Fiber; Data; Day Surgery; Deposition; Development; Drug Delivery Systems; Erinaceidae; Fibrocartilages; Future; Genes; Genetic; Growth and Development function; Injury; Knowledge; LacZ Genes; Lasers; Lead; Ligaments; Measures; Mechanics; Mesenchymal Stem Cells; Methods; Minerals; Modeling; Mus; Operative Surgical Procedures; Osteocytes; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Process; Production; Proteoglycan; Reporter; Reporting; Role; Scientist; Series; Signal Pathway; Site; Sports Medicine; Surgical Models; Tamoxifen; Tendon Injuries; Tendon structure; Testing; Therapeutic; Time; Tissues; Transgenic Mice; antagonist; anterior cruciate ligament reconstruction; bone; bone repair; gain of function; healing; improved; innovation; ligament injury; loss of function; mouse model; musculoskeletal injury; novel; novel therapeutics; progenitor; reconstruction; repair model; repaired; response; smoothened signaling pathway; spatiotemporal; tendon graft

Summary Approximately 30% of U.S. adults suffer from tendon and ligament injuries, which frequently occur near insertion sites into bone (i.e., entheses) and do not spontaneously heal. Growth and development studies have demonstrated a critical role for hedgehog (Hh) signaling in driving zonal enthesis formation but it's role in adult enthesis repair is largely unknown. Zonal enthesis formation involves anchoring collagen fibers, synthesizing proteoglycan-rich fibrocartilage, and mineralizing this fibrocartilage. Hh promotes this fibrocartilage formation. Unfortunately, studying this pathway in traditional tendon-to-bone repair has been a challenge since these repair models do not sufficiently anchor collagen fibers to bone, much less produce zones of fibrocartilage. Conversely, ligament reconstructions, where a tendon graft is placed through bone tunnels, can produce zonal attachments. Therefore, ligament reconstruction models, such as the anterior cruciate reconstruction model proposed in this application, can be employed to study the mechanisms that regulate zonal tendon-to-bone repair in the adult. This proposal will address this gap in knowledge by targeting the hedgehog pathway genetically and pharmacologically during tendon-to-bone repair following ACL reconstruction in novel transgenic mouse models. We will define the roles of the hedgehog pathway in specific stages of the repair response from the expansion of the progenitor pool to production of fibrocartilage and bone within zonal tendon-to-bone attachments during the tunnel integration process. By modulating the pathway pharmacologically, we will determine the potential for this pathway to be targeted in a translational fashion that could lead to novel therapies in the future. Our central hypothesis is that the Hh pathway is a critical positive regulator of zonal enthesis formation in the adult and therefore stimulation of the pathway will improve tendon- to-bone repair.

概括 大约 30% 的美国成年人患有肌腱和韧带损伤，这些损伤经常发生在身体附近 插入部位进入骨骼（即附着点）并且不会自发愈合。生长和发育研究 证明了刺猬蛋白 (Hh) 信号在驱动带状附着点形成中的关键作用，但它在成体中的作用 附着点修复在很大程度上是未知的。带状附着点形成涉及锚定胶原纤维、合成 富含蛋白聚糖的纤维软骨，并使该纤维软骨矿化。 Hh 促进这种纤维软骨的形成。 不幸的是，研究传统肌腱-骨修复中的这条途径一直是一个挑战，因为这些 修复模型无法将胶原纤维充分锚定到骨骼上，更不用说产生纤维软骨区域了。 相反，韧带重建（即通过骨隧道放置肌腱移植物）可以产生带状韧带 附件。因此，韧带重建模型，如前交叉韧带重建模型 本申请中提出的，可用于研究调节带状肌腱到骨的机制 修复于成人。该提案将通过针对刺猬途径来解决这一知识差距 新型 ACL 重建后肌腱至骨修复过程中的遗传和药理学研究 转基因小鼠模型。我们将定义刺猬通路在修复的特定阶段的作用 祖细胞池扩张对区域内纤维软骨和骨产生的反应 隧道整合过程中肌腱与骨骼的连接。通过调节途径 在药理学上，我们将确定该途径以转化方式靶向的潜力， 未来可能会带来新的疗法。我们的中心假设是 Hh 通路是一个关键的正向通路 成人带状附着点形成的调节器，因此刺激该通路将改善肌腱 到骨修复。