Regulation of tendon development by CCN1/Cyr61

CCN1/Cyr61 对肌腱发育的调节

• 批准号: 9319576
• 负责人: Karen M. Lyons
• 金额: $ 16.94万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-10 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319576
• 关键词: Adult; Affect; Age; Alpha Cell; Anterior Cruciate Ligament; Behavior; Cartilage; Cell Proliferation; Cells; Characteristics; Cicatrix; Congenital Abnormality; Congenital clubfoot; Data; Defect; Deformity; Development; Disease; Engineering; Exhibits; Extracellular Matrix; Family; Fibroblasts; Fibrosis; Future; Gait; Gene Expression; Gene Expression Profile; Histologic; In Vitro; Inferior; Ligaments; Limb structure; Maintenance; Mechanics; Molecular; Mus; Muscle; Musculoskeletal System; Pathway interactions; Phenotype; Play; Proteins; Recurrence; Regulation; Role; Stem cells; Tendon Injuries; Tendon structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Thick; Tissues; achilles tendon; bone; common treatment; expectation; flexibility; healing; in vivo; injury and repair; mechanical properties; member; mutant; patellar tendon; postnatal; prevent; progenitor; senescence; success; tendon development; transcriptome sequencing; wound

PROJECT SUMMARY The mechanisms underlying tendon development are by far the least understood of any component of the musculoskeletal system. This is a concern because tendon injuries are common and treatment options are limited. Healing often results in formation of scar tissue, which is compositionally and mechanically inferior to native tendon, resulting in decreased flexibility and a high recurrent tear rate. Members of the CCN family of matricellular proteins have been extensively studied due to their key roles in multiple fibrotic conditions, but their roles in normal fibrous tissues like tendons are unknown. We found that CCN1/Cyr61 s highly expressed in tendon and ligament, and that mice in which Ccn1 is ablated in tendon/ligament progenitor stem cells (TPSCs) using Scx-Cre (Ccn1SKO) exhibit a clubfoot-like phenotype. Histological analysis revealed that anterior cruciate ligament (ACL), Achilles and patellar tendons are substantially thicker and more stout than in wild-type (WT) littermates at birth; these defects persist in adults. The affected tendon displays stronger mechanical properties early, but becomes significantly weaker with age. No other mutants with a similar phenotype have been described to date. Initial RNA-Seq and phenotypic analysis revealed that affected tendons in Ccn1SKO mice acquire a gene expression profile similar to that of activated wound fibroblasts. We therefore have a unique opportunity to identify new mechanisms regulating tendon formation and remodeling that have direct therapeutic potential. We plan to: 1) define the function of CCN1/Cyr61 in tendon formation and maintenance in vivo through phenotypic analysis of Ccn1SKO mice, and 2) test the hypothesis that CCN1/Cyr61 is required in TPSCs/tenocytes to promote the tenogenic phenotype and prevent acquisition of an activated wound fibroblast fate. Success with these studies would provide a strong rationale for future studies that evaluate the function of CCN1/Cyr61 in tendon injury/repair and develop CCN1/Cyr61 as a therapeutic agent to promote scarless tendon healing.

项目摘要 迄今为止，肌腱发育的基础机制在任何组成部分中最不了解 肌肉骨骼系统。这是一个问题，因为肌腱受伤很常见，治疗方案是 有限的。愈合通常会导致疤痕组织的形成，疤痕组织在组成和机械上都不优于 天然肌腱，导致柔韧性降低和较高的反复撕裂率。 CCN家族的成员 由于其在多种纤维化条件中的关键作用，因此对母细胞蛋白进行了广泛的研究，但 它们在正常纤维组织（如肌腱）中的作用尚不清楚。我们发现CCN1/CYR61 S高度表达 在肌腱和韧带中，在肌腱/韧带祖细胞中烧蚀了CCN1的小鼠 （TPSC）使用SCX-CRE（CCN1SKO）表现出类似俱乐部的表型。组织学分析表明前方 与野生型相比 （wt）出生时同窝仔；这些缺陷在成年人中仍然存在。受影响的肌腱显示更强的机械 早期属性，但随着年龄的增长而变得明显弱。没有其他具有类似表型的突变体具有 迄今已被描述。最初的RNA-seq和表型分析表明，CCN1SKO中的肌腱影响 小鼠获得类似于活化伤口成纤维细胞的基因表达谱。因此，我们有一个 独特的机会来确定调节肌腱形成和重塑的新机制 治疗潜力。我们计划：1）在肌腱形成和维护中定义CCN1/CYR61的功能 通过CCN1SKO小鼠的表型分析在体内，2）检验以下假设：CCN1/CYR61在 tpsc/tenocytes以促进替代性表型并防止恢复活化的伤口成纤维细胞 命运。这些研究的成功将为未来的研究提供强大的理由，以评估 肌腱损伤/修复中的CCN1/CYR61并发展为CCN1/CYR61作为治疗剂，以促进无疤 肌腱愈合。