Osteoprogenitor mobilization for bone development and repair

骨祖细胞动员以促进骨骼发育和修复

基本信息

批准号：
10614547
负责人：
Joel D Boerckel
金额：
$ 34.54万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614547
关键词：
Affect Bone Development Bone Transplantation Bone callus Breeding Cartilage Cell Proliferation Cells Clinical Collagen Collagen Gene Complication Cytoskeleton Data Defect Development Developmental Bone Diseases Embryo Environment Excision Feedback Fracture Genetic Transcription Goals Image Impairment In Vitro Intervention Knockout Mice Limb Development Limb structure Mechanics Mediating Mesenchymal Modeling Molecular Mus Natural regeneration Osteogenesis Pathway interactions Physiologic Ossification Positioning Attribute Primary Ossification Center Process Production Proliferating Proteins Qualifying Regulation Reporter Reporter Genes Research Role Testing Tissue Engineering Tissues Transcription Coactivator Transgenic Organisms Traumatic injury X-Ray Computed Tomography biomechanical test bone bone fracture repair bone repair cell motility clavicle combinatorial conditional knockout contrast enhanced design experimental study healing in vivo innovation insight intramembranous bone formation mechanical load mechanical signal mechanotransduction microCT migration osteoblast differentiation osteogenic osteoprogenitor cell progenitor programs recruit repaired sample fixation spatiotemporal stem cells success tumor

项目摘要

Abstract Large bone defects caused by traumatic injury or tumor resection pose a significant clinical challenge as they cannot not heal without intervention, and current bone grafting therapies are limited. Tissue engineering is a promising alternative, but is often limited by poor recruitment or supply of endogenous progenitor cells. Unlike large defects, bone fractures heal readily by recapitulating the steps of bone development. In fracture repair, mechanical cues, in the form of interfragmentary strains, are essential to determine the pathway by which bone formation occurs, namely direct bone formation through intramembranous ossification or indirect bone formation through endochondral ossification, in which a cartilage template forms first and is later replaced by bone. The mechanisms by which osteoprogenitor cells are mobilized during bone development and how mechanical cues direct fracture repair are poorly understood. We observed combinatorial roles of the mechanosensitive transcriptional co-activators, Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-motif (TAZ) in promoting both bone development and repair. The goal of this application is to define the mechanistic roles of YAP/TAZ in osteoprogenitor cell mobilization during bone development and mechanical load-mediated fracture repair. Accomplishing this goal will provide new insights into developmental bone diseases, identify pathways that could be exploited to enhance healing, and position us to design new tissue engineering strategies that recapitulate the processes of bone development and natural repair for regeneration of large bone defects.

抽象的由外伤或肿瘤切除引起的大骨缺损构成了重大的临床挑战，因为它们如果不进行干预就无法愈合，并且目前的骨移植疗法是有限的。组织工程是一门有前途的替代方案，但往往受到内源祖细胞招募或供应不良的限制。不像大的缺损、骨折通过重演骨骼发育的步骤很容易愈合。在骨折修复中，以片段间应变形式出现的机械线索对于确定骨的形成途径至关重要发生形成，即通过膜内骨化直接骨形成或间接骨形成通过软骨内骨化形成，其中软骨模板首先形成，然后被替换骨。骨发育过程中骨祖细胞动员的机制以及如何人们对直接骨折修复的机械线索知之甚少。我们观察到的组合作用机械敏感转录共激活因子、Yes 相关蛋白 (YAP) 和转录共激活因子含有 PDZ 基序 (TAZ)，可促进骨骼发育和修复。该应用程序的目标是定义 YAP/TAZ 在骨发育过程中骨祖细胞动员中的机制作用机械负荷介导的骨折修复。实现这一目标将为发展提供新的见解骨疾病，确定可用于增强愈合的途径，并使我们能够设计新的组织工程策略概括了骨骼发育和自然修复的过程大骨缺损的再生。