Injury Response in Normal and EDS Tendons: Regulatory Roles of Collagen V

正常肌腱和 EDS 肌腱的损伤反应：V 型胶原蛋白的调节作用

• 批准号: 8669381
• 负责人: DAVID E BIRK
• 金额: $ 35.29万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669381
• 关键词: Affect; Architecture; Area; Chronic; Collagen; Collagen Fibril; Connective Tissue; Coupled; Data; Data Analyses; Defect; Deposition; Development; Ehlers-Danlos Syndrome; Fatigue; Fiber; Flexor; Foundations; Future; Gait abnormality; Goals; Healed; Impairment; Individual; Inflammatory; Injury; Joint Dislocation; Joint Instability; Joint Laxity; Ligaments; Link; Measures; Mechanics; Mediating; Minor; Modality; Modeling; Molecular; Mus; Mutation; Performance; Phase; Phenotype; Property; Role; Skin; Structure; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Therapeutic Intervention; Time; Tissue Engineering; Up-Regulation; Work; Wound Healing; anterior cruciate ligament rupture; base; comparative; healing; heritable connective tissue disorder; innovation; mouse model; public health relevance; repaired; response; response to injury; therapy design; wound

DESCRIPTION (provided by applicant): The overall goal of this proposal is to define the regulatory roles of collagen V in the injury response in normal and classic Ehlers-Danlos syndrome (EDS) tendons. Collagen V is a quantitatively minor component of collagen fibrils, yet modulation of its expression has dramatic phenotypic effects, indicating critical regulatory roles. EDS is a heritable connective tissue disorder with generalized connective tissue fragility and the classic form is characterized by hyperextensible skin, joint laxity and instability, as well as abnormal wound healing. Classic EDS is defined by collagen V mutations with haploinsufficiency for COL5A1 present in ~67% of affected individuals. Collagen V also has been linked to: Achilles tendinopathy, ACL rupture, as well as injury and performance deficiencies. In addition, upregulation of collagen V is observed in the injury response in tendons and ligaments. Our established haploinsufficent collagen V EDS mouse model will be used for the proposed studies. However, this model has limitations due to chronic effects resulting from lack of collagen V throughout development and maturation that are then superimposed on the changes associated with the injury response. Therefore, this proposal incorporates our inducible collagen V-null and heterozygous models that allow for temporal targeting of the modulation of collagen V expression. For the first time, directly studying the critical regulatory roles of collagen V during specific phases of the injury response will be possible. Using the haploinsufficient collagen V EDS model, we have demonstrated reduced fibril number, abnormal fibril structure, decreased cross sectional area, and a reduction in the stiffness of the flexor digitorum longus tendon consistent with the hypermobile EDS phenotype. Our recent work using a conditional null model demonstrated severe structural alterations at the fibril, fiber and tendon level associated with severely compromised mechanical function, joint dislocations and gait abnormalities. The general hypothesis tested in this proposal is that the tendon response to injury is modulated by collagen V mediated mechanism(s). The aims are to: (Aim 1) Define the altered regulatory function(s) of collagen V in the abnormal tendon injury response in classic EDS~ (Aim 2) Elucidate the mechanistic regulatory role(s) of collagen V in the repair response to tendon injury in a normal matrix~ and (Aim 3) Compare the effect of modulation of collagen V expression on the injury response in normal and in diseased/abnormal tendons. Our innovative approach with both conventional and inducible mouse models will systematically analyze the regulatory roles of collagen V on repair of tendon injuries. This approach will be coupled with sophisticated and innovative measures of mechanical and organizational properties, together with compositional profiles, to derive a mechanistic understanding of the injury responses. These studies will define the specific temporal regulatory roles of collagen V in the re- establishment of tendon structure and function in response to injury. In addition, the data will provide a critical foundation for developing therapeutic interventions to enhance the abnormal wound healing in EDS.

描述（由申请人提供）：该提案的总体目标是定义胶原蛋白V在正常和经典的Ehlers-Danlos综合征（EDS）肌腱中胶原蛋白V的调节作用。胶原蛋白V是胶原原纤维的定量成分，但对其表达的调节具有显着的表型作用，表明调节作用的关键作用。 EDS是一种可遗传的结缔组织障碍，具有普遍的结缔组织脆弱性，经典形式的特征是皮肤过度，关节松弛和不稳定以及伤口异常的愈合。 经典ED是由约67％受影响个体的COL5A1的胶原V突变定义的。胶原V还与：跟腱病，ACL破裂以及损伤和性能不足有关。另外，在肌腱和韧带的损伤反应中观察到胶原蛋白V的上调。我们已建立的单倍胶胶原V EDS小鼠模型将用于拟议的研究。但是，由于在整个发育和成熟过程中缺乏胶原蛋白V产生的慢性影响，因此该模型的局限性被叠加在与损伤反应相关的变化上。因此，该提案结合了我们诱导的胶原蛋白V-null和杂合模型，这些模型允许时间靶向胶原V表达的调节。首次可以直接研究胶原蛋白V在损伤反应的特定阶段的关键调节作用。使用单倍体胶原蛋白V EDS模型，我们证明了原纤维数量减少，原纤维结构异常，横截面面积降低以及屈肌长长肌腱与HyperMobile ED Sypys一致的刚度降低。我们最近使用条件无效模型的工作表明，与严重损​​害的机械功能，关节位错和步态异常相关的原纤维，纤维和肌腱水平的严重结构改变。该提案中检验的一般假设是肌腱对损伤的反应是通过胶原蛋白V介导的机制调节的。目的是：（目标1）在经典EDS〜（AIM 2）中定义胶原蛋白V的调节功能的改变（S）在正常基质中对肌腱损伤的修复响应中的机理调节作用（AIM 2）在正常基质和（AIM 3）中的肌腱损伤响应中的肌腱损伤反应的效应在胶原膜上的效应中表现出正常的效应，并且在肌腱损伤中表达了正常的效应。我们使用常规小鼠模型和诱导小鼠模型的创新方法将系统地分析胶原蛋白V修复肌腱损伤的调节作用。这种方法将与机械和组织特性的复杂和创新度量以及组成曲线相结合，以获取对伤害反应的机械理解。这些研究将定义胶原蛋白V在肌腱结构建立和功能响应损伤中的特定时间调节作用。此外，数据将为开发治疗性干预措施提供关键基础，以增强ED中的异常伤口愈合。