Ephrin Therapy for Segmental Defect Repair in Bone

Ephrin 疗法修复骨节段性缺损

• 批准号: 8925594
• 负责人: Charles Rundle
• 金额: --
• 依托单位: VA LOMA LINDA HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925594
• 关键词: Aging; Binding; Bone Injury; Bone Regeneration; Bone callus; Cell Lineage; Characteristics; Clinical; Closed Fractures; Data; Defect; Development; Economic Burden; Economics; Eph Family Receptors; Ephrin B Receptor; Ephrins; Exhibits; Femoral Fractures; Femur; Fracture; Fracture Healing; Future; Gene Targeting; Genes; Healed; Hospitalization; Impaired health; Impairment; Injury; Investigation; Knockout Mice; Laboratories; Lead; Length; Lentivirus Vector; Ligands; Mechanical Stress; Mechanics; Mediating; Modeling; Molecular; Morbidity - disease rate; Motion; Mus; Orthopedics; Osteoblasts; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Physiological; Play; Proliferating; Regulation; Research; Role; Signal Pathway; Signal Transduction; Societies; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Wild Type Mouse; angiogenesis; base; bone; bone cell; bone healing; clinically relevant; effective therapy; gene therapy; healing; improved; innovation; insight; long bone; microCT; mutant; novel; osteoblast differentiation; overexpression; postnatal; public health relevance; receptor; repaired; response; sample fixation; skeletal; small molecule

 DESCRIPTION (provided by applicant): Skeletal fractures of the long bones are a major orthopedic problem. Skeletal healing is impaired in 10- 20% of these fractures, resulting in nonunion or delayed union healing. This constitutes a highly significant morbidity to patients, prolonged hospitalizations, and a huge economic burden for the patient and society. Thus, it is highly desirable to have an effective treatment to promote bone healing in conditions where the injury is so severe that normal healing is not possible, or in otherwise normal fracture healing impaired by health-related conditions. A robust periosteal response is critical for efficient bone healing. We have developed significant preliminary evidence that ephrin (efn) B1 signaling regulates bone formation and promotes a substantial periosteal response to mechanical loading and fracture repair. Accordingly, we have proposed that efnB1 promotes the periosteal response to loading and injury, and that this periosteal response can be used to enhance the healing of segmental defect injuries. Our laboratory has also recently developed a novel model of segmental bone injury in the mouse femur that is a better paradigm of endochondral bone repair and is more clinically relevant to impaired fracture healing than the commonly used closed fracture models or rigid external fixation approaches to segmental defects. This defect model fails to heal well after it should have achieved bony union, and therefore represents a very challenging model of bone repair to investigate efnB1 regulation of bone healing. Three specific objectives are proposed to test efnB1 regulation of bone repair using this model. 1) To test the hypothesis that efnB1 regulates bone repair in a femoral segmental defect model of bone healing, we will characterize impaired segmental defect healing in a transgenic efnB1 mouse line that overexpresses efnB1 specifically in osteoblast lineage cells. 2) To test the hypothesis that efnB1 enhancement of healing in a segmental defect model of bone repair is regulated by efnB1 reverse signaling that is induced upon efnB1 contact with its receptors (eph), we will examine segmental defect repair in osteoblast-specific efnB1 knockout mice, but selectively restore forward and reverse signaling or only forward signaling by the transduction of appropriate efnB1 gene constructs. These constructs will be either a full-length wild-type efnB1 capable of forward and reverse signaling, or a truncated efnB1 with a defective signaling domain that eliminates reverse signaling. 3) To test the hypothesis that efnB1 therapy can promote the healing of non-union femoral segmental defects, we will utilize the signaling regulation identified in the second specific objective to aply efnB1 and ephB2 gene therapy to the femoral segmental defect of wild-type mice and evaluate healing. Our proposed studies will improve our understanding of ephrin regulation of bone repair in a severely impaired model of healing and evaluate efnB1 therapy as an approach for the improvement of bone healing impaired by clinically challenging injuries, as well by physiological conditions such as osteoporosis.

 描述（由申请人提供）： 长骨的骨骼骨折是一个主要的骨科问题，其中 10-20% 的骨折会损害骨骼愈合，导致骨不连或愈合延迟，这对患者造成严重的发病率、长期住院和巨大的经济负担。因此，对于患者和社会来说，在损伤严重以致无法正常愈合的情况下，或者在因健康相关因素而损害正常骨折愈合的情况下，非常需要一种有效的治疗方法来促进骨愈合。强大的骨膜反应对于有效的骨愈合至关重要。我们的实验室最近还开发了一种新的小鼠节段性骨损伤模型。股骨是软骨内骨修复的更好范例，并且与常用的闭合骨折模型或节段缺损的刚性外固定方法相比，在临床上与骨折愈合更相关。这种缺损模型在应该实现骨性愈合后未能很好地愈合，因此，这是一个非常具有挑战性的骨修复模型，用于研究 efnB1 对骨愈合的调节。提出了三个具体目标，以使用该模型测试 efnB1 对骨修复的调节1) 检验 efnB1 调节骨修复的假设。在骨愈合的股骨节段缺损模型中，我们将表征转基因 efnB1 小鼠系中受损的节段缺损愈合，该转基因 efnB1 小鼠系在成骨细胞谱系细胞中特异性过度表达 efnB1 2) 检验 efnB1 增强骨节段缺损模型中愈合的假设。修复受 efnB1 反向信号传导调节，该信号传导是在 efnB1 与其受体 (eph) 接触时诱导的，我们将检查成骨细胞特异性的节段性缺损修复efnB1 敲除小鼠，但通过转导适当的 efnB1 基因构建体选择性恢复正向和反向信号传导或仅恢复正向信号传导。这些构建体将是能够正向和反向信号传导的全长野生型 efnB1，或具有消除反向信号传导的缺陷信号传导域 3) 为了检验 efnB1 疗法可以促进不愈合股骨节段缺损愈合的假设，我们将利用第二个具体目标是将 efnB1 和 ephB2 基因疗法应用于野生型小鼠的股骨节段缺损并评估愈合情况，我们提出的研究将提高我们对严重受损模型中骨修复的肝配蛋白调节的理解。评估 efnB1 疗法作为改善因临床挑战性损伤以及骨质疏松等生理状况而受损的骨愈合的方法。