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.

项目总结 肌腱发育的机制是迄今为止对肌腱发育的所有组成部分中了解最少的 肌肉骨骼系统。这是一个令人担忧的问题，因为肌腱损伤很常见，治疗方案是 有限的。愈合通常会导致疤痕组织的形成，而疤痕组织的成分和机械性能不如 原生肌腱，导致柔韧性下降，复发性撕裂率高。CCN家族的成员 基质细胞蛋白因其在多种纤维化条件下的关键作用而被广泛研究，但是 它们在肌腱等正常纤维组织中的作用尚不清楚。我们发现CCN1/Cyr61 S高度表达 在肌腱和韧带中，以及在肌腱/韧带前体干细胞中CCN1被去除小鼠 使用SCX-CRE(Ccn1SKO)的(TPSCs)表现出马蹄内翻足样表型。组织学分析显示，前部 与野生型相比，十字韧带(ACL)、跟腱和髌腱实质上更厚、更结实 (WT)出生时产仔；这些缺陷在成人中持续存在。受影响的肌腱显示出更强的机械性 早期的特性，但随着年龄的增长变得明显减弱。没有其他具有类似表型的突变体 到目前为止都被描述过。初步的RNA-Seq和表型分析显示，Ccn1SKO中的肌腱受到影响 小鼠获得了类似于激活的伤口成纤维细胞的基因表达谱。因此，我们有一个 独一无二的机会来确定调控肌腱形成和重塑的新机制，这些机制直接 治疗潜力。我们计划：1)明确CCN1/Cyr61在肌腱形成和维持中的作用 通过对Ccn1SKO小鼠的表型分析，以及2)验证CCN1/Cyr61在体内需要的假设 TPSCs/Tencell促进肌腱形成表型和防止获得活化的伤口成纤维细胞 命运。这些研究的成功将为未来评估脑血管紧张素转换酶功能的研究提供强有力的理论基础。 CCN1/Cyr61在肌腱损伤/修复中的作用及其作为促进无瘢痕形成的治疗药物 肌腱愈合。