A Systems Genetics Approach to Fracture Healing

说明(申请人提供)：骨折是最常见的大器官损伤之一，与骨质疏松症相关的骨折是老龄化发展最快的医疗保健问题。骨折愈合可以被认为是一种复杂的特征，其定义是机械能力的恢复，从而允许恢复负重。作为一种复杂的特征，骨折愈合是多种细胞类型功能贡献的结果。许多个体的表型特征，如矿化组织的数量和愈伤组织的结构，促成了这一复杂的特征，并且每个特征都受到多种遗传和环境因素之间的相互作用的影响。我们的假设是，可以使用系统网络方法来研究不同遗传和环境条件下的骨折愈合，以确定导致这一复杂特征的中心因素。骨折愈合的环境变异性将用甲状旁腺激素(PTH)治疗和磷酸盐缺乏(模拟软骨病和抑制愈合)来模拟，甲状旁腺激素(PTH)治疗可以促进愈合。骨折愈合中的遗传变异性将使用三种近亲交配的小鼠品系进行建模，这些品系的骨骼质量差异具有很好的特征。提出的工作的第一个目标是建立愈伤组织的特定结构特征、细胞和组织类型以及特定结构特征之间的功能关系。 有助于骨折骨的机械性能恢复速度的生物过程。这将通过组织学分析、微型计算机断层扫描和生物力学测试来实现，以量化骨折骨痂在器官、组织和细胞水平上的表型特性的时间变化。然后将使用多元回归分析和通径分析来确定不同表型特性之间的功能依赖关系以及它们与恢复强度的关系。第二个目标是确定哪些差异表达的基因有助于骨折愈合作为一种特征。将使用全球转录图谱和多种生物信息学方法来确定在骨折愈合过程中以及因遗传变异和环境干扰而改变的主要转录因子、生物和分子过程以及信号转导途径。差异表达的基因组和各种表型属性之间的因果关系将被识别，并将被用来定义控制这些表型属性的分子功能。总而言之，这些研究将确定临床上可用于评估愈合的相关性和促进愈合的分子靶点。 公共卫生相关性：骨折是人类最常见的大器官创伤，与骨质疏松症相关的骨折是老龄化中增长最快的医疗保健问题。这项建议旨在从整体、器官组织和分子水平定义最能定义骨折愈合的属性。所有拟议研究的结果都将对制定骨折愈合的诊断和预后指标以及开发促进骨折愈合的新的治疗方案具有临床意义。

DESCRIPTION (provided by applicant): Fractures are one of the most common large-organ, traumatic injuries, and osteoporosis-related fractures are the fastest growing health care problem of aging. Fracture healing can be considered a complex trait that is defined by the regain in mechanical competence that allows resumption of weight bearing. As a complex trait, fracture healing is the result of the functional contributions of multiple cell types. Many individal phenotypic properties, such as the amount of mineralized tissue and structure of the callus, contribute to this complex trait, and each property is affected by interactions between multiple genetic and environmental factors. Our hypothesis is that a systems-network approach to the study of fracture healing under differing genetic and environmental conditions can be used to identify the central elements that contribute to this complex trait. Environmental variability of fracture healing will be modeled using parathyroid hormone (PTH) treatment, which enhances healing, and phosphate deficiency, which mimics rickets and inhibits healing. Genetic variability in fracture healing will be modeled using three inbred strains of mice with well characterized differences in bone quality. The first aim of the proposed work is to establish the functional relationships among specific structural features of the callus, cell and tissue types, and specific biological processes that contribute to the rate of regain of the mechanical properties of the fractured bone. This will be achieved by histological analysis, micro- computed tomography, and biomechanical testing to quantify the temporal changes in phenotypic properties of the fracture callus at the organ-, tissue-, and cellular levels. Multivariate regression analyses and path analyses will then be used to identify the functional dependencies among various phenotypic properties and to their relationship to regain in strength. The second aim is to identity the differentially expressed genes that contribute to fracture healing as a trait. Global transcriptionl profiling and multiple bioinformatics approaches will be used to define the primary transcription factors, biological and molecular process, and signal transduction pathways that are altered during fracture healing and in response to genetic variability and environmental perturbation. The causal relationships between the differentially expressed genes groups and the various phenotypic properties will be identified and will be used to define the molecular functions that control these phenotypic properties. In aggregate, these studies will identify both clinically useable correlates to assess healing and molecular targets to promote healing. PUBLIC HEALTH RELEVANCE: Fractures are the most common large-organ, traumatic injuries in humans, and osteoporosis-related fractures are the fastest growing health care problem of aging. This proposal is directed at defining at whole, organ tissue, and molecular levels the properties that best define fracture healing. All of the findings from the proposed studies will have clinical bearing towards the development of diagnostic and prognostic indices of fracture healing and the development of new therapeutic options to promote fracture healing.