Molecular Mechanisms of Skeletal Repair

描述(由申请人提供)： 骨骼修复是骨科和肌肉骨骼护理的许多方面的基本过程，从骨折治疗到脊柱和四肢的重建手术。目前的估计表明，5%-10%的骨折愈合延迟或受损，5%-30%的脊柱融合无法愈合，全球每年进行的植骨手术数量超过150万例。因此，虽然关于骨修复过程的生物学已经学到了很多，但我们的知识仍然存在很大差距，需要制定促进骨骼愈合和再生的策略。这项应用将涵盖细胞和分子生物学、生物医学工程和代谢性骨骼疾病等领域，以提供关于骨骼修复的协调、集成的研究计划。在这些领域都有专长的科学家将相互作用，以相互获取知识并协同发展概念和想法。该科学计划由3个项目和4个核心组成。这些项目将通过牵张成骨模型阐明骨再生中血管生成的机制，使用一种新的转基因模型阐明BMPs在骨折愈合中的作用，在该模型中，小分子调节的蛋白质二聚体被用来特异性地激活转录因子，使我们能够以条件和组织特异性的方式表达noggin(BMP功能的抑制物)或BMP2，以及以糖尿病为模型系统的代谢失调对骨折愈合的影响。这些核心将提供服务和数据库，以加强项目的发展。基因组学和信息学核心将加强项目间数据的收集、组织和共享。将通过组织形态计量学和生物力学核心建立一个进行骨骼愈合标准化测量的中央设施。细胞和分子生物学核心将为细胞和分子生物试剂的开发和维护提供一个集中的设施，并确保我们所有手术模型的统一质量控制。最后，将通过行政核心对方案指示和资金进行监督和管理，并协调内部和外部委员会的咨询意见。该计划旨在通过具有互补和协同科学协会记录的研究人员团队的综合和合作活动，建立对骨骼修复机制的更深刻理解。这一计划的成功建立和实施将极大地加强这一研究团队的协调活动，并为骨骼愈合研究带来重要的新成果和方向。

DESCRIPTION (provided by applicant): Skeletal repair is a fundamental process that underlies many aspects of orthopaedic and musculoskeletal care ranging from fracture treatment to reconstructive surgery of the spine and extremities. Current estimates indicate that 5-10% of fractures experience delayed or impaired healing, 5-30% of spinal fusions fail to unite and the number of bone graft procedures performed worldwide exceeds 1.5 million per year. Thus while much has been learned regarding the biology of the bone repair process, significant gaps remain in our knowledge and a need exists for the development of strategies to enhance skeletal healing and regeneration. This application will cover areas of cell and molecular biology, biomedical engineering, and metabolic bone disease to provide a coordinated, integrated program of investigations on skeletal repair. Scientists with expertise in each of these domains will interact for the mutual gain of knowledge and synergistic development of concepts and ideas. The scientific program is composed of 3 projects and 4 cores. The projects will elucidate the mechanisms of angiogenesis in bone regeneration using a model of distraction osteogenesis, the role of BMPs in fracture healing using a novel transgenic model in which small-molecule-regulated protein dimerization is used to specifically activate a transcription factor that allows us to express noggin (an inhibitor of BMP function) or BMP2 in both in a conditional and tissue specific manner, and the effects of metabolic dysregulation on fracture healing using diabetes as a model system. The cores will provide services and databases to enhance the development of the projects. The genomics and informatics core will enhance the collection, organization and sharing of data among projects. A centralized facility for carrying out standardized measurements of skeletal healing will be established through the histomorphometry and biomechanics core. The cellular and molecular biology core will provide a centralized facility for the development and maintenance of the cellular and molecular biological reagents as well insure uniform quality control for all our surgical models. Finally, oversight and management of programmatic directives and funds and coordination of advisory input from the internal and external committees will be provided through the administrative core. The program intends to establish a more profound understanding of skeletal repair mechanisms through the integrative and collaborative activities of a team of investigators who have a track record of complimentary and synergistic scientific associations. Successful establishment and implementation of this program will greatly enhance the coordinated activities of this team of investigators and lead to important new results and directions for skeletal healing research.