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.

总结 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 插入骨的位置（即，附着点）并且不能自发愈合。生长发育研究 证明了刺猬（Hh）信号在驱动带状附着点形成中的关键作用，但它在成人中的作用 附着点修复在很大程度上是未知的。带状附着点的形成包括固定胶原纤维，合成 富含蛋白多糖的纤维软骨，并使该纤维软骨矿化。促进这种纤维软骨的形成。 不幸的是，在传统的肌腱-骨修复中研究这一途径一直是一个挑战，因为这些 修复模型不能充分地将胶原纤维锚在骨上，更不用说产生纤维软骨区。 相反，韧带重建，其中肌腱移植物放置通过骨隧道，可以产生带状 附件的权限.因此，韧带重建模型，例如前交叉韧带重建模型， 在本申请中提出，可用于研究调节带状腱-骨的机制， 修复成人这项提案将通过针对刺猬途径来解决这一知识缺口 在新的ACL重建后的肌腱-骨修复过程中， 转基因小鼠模型。我们将定义刺猬途径在修复的特定阶段的作用 从祖细胞库的扩张到带状内纤维软骨和骨的产生的反应 在隧道整合过程中的肌腱-骨连接。通过调节 因此，我们将确定该途径以翻译方式靶向的潜力， 可能会在未来带来新的治疗方法。我们的中心假设是，Hh途径是一个关键的积极因素， 成人中带状附着点形成的调节剂，因此刺激该通路将改善肌腱- 骨修复