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。这些骨折的10-20％会损害骨骼愈合，导致骨不连或延迟的联合愈合。这构成了对患者，长期住院治疗以及患者和社会的巨大经济燃烧的高度显着发病。这是非常需要有效的治疗方法来促进损伤如此严重以至于无法正常愈合或在其他正常骨折愈合受到健康相关状况损害的情况下促进骨骼愈合的方法。稳健的骨膜反应对于有效的骨骼愈合至关重要。我们已经开发了大量的初步证据，表明ephrin（EFN）B1信号传导调节骨骼形成，并促进对机械负荷和断裂修复的大量骨膜反应。根据，我们提出EFNB1促进了骨膜对负荷和损伤的反应，并且该骨膜反应可用于增强分段缺陷损伤的愈合。我们的实验室最近还开发了一种新型的小鼠股骨骨损伤模型，该模型是内软骨修复的更好的范式，并且比常用的闭合闭合断裂模型或刚性外部固定方法在临床上与骨折愈合受损更相关。该缺陷模型​​在应该达到邦迪联合后无法恢复良好，因此代表了骨修复的非常挑战的模型，以研究EFNB1骨骼愈合的调节。提出了三个特定的目标，用于使用此模型测试骨修复的EFNB1调节。 1）为了测试EFNB1在股骨愈合的骨骼节段性缺陷模型中调节骨修复的假设，我们将表征转基因EFNB1小鼠系列中的节段缺陷愈合受损，从而过度表达了成骨细胞谱系中EFNB1的过度表现。 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 translation of appropriate EFNB1基因构建体。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，或者是具有有缺陷的信号传导域的截断EFNB1，可以消除反向信号传导。 3）为了检验EFNB1治疗可以促进非股骨分段缺陷的愈合的假设，我们将利用在ALY EFNB1和EPHB2基因疗法的第二个特定目标中确定的信号调节，以使其对蛋白型小鼠的股骨分段缺陷进行野生型小鼠的股骨分段缺陷。我们提出的研究将在严重受损的愈合模型中提高对骨修复的晶状体调节的理解，并评估EFNB1治疗，作为改善骨骼挑战损伤损害骨骼治疗的方法，以及诸如骨质疏松症等身体状况。