A Systems Genetics Approach to Fracture Healing

描述（由申请人提供）：骨折是最常见的大器官、外伤性损伤之一，骨质疏松相关骨折是增长最快的老年保健问题。骨折愈合可以被认为是一种复杂的特征，其定义为机械能力的恢复，允许恢复负重。作为一种复杂的特性，骨折愈合是多种细胞类型功能共同作用的结果。许多个体表型特性，如矿化组织的数量和愈伤组织的结构，都有助于这种复杂的性状，每一种特性都受到多种遗传和环境因素之间相互作用的影响。我们的假设是，在不同遗传和环境条件下研究骨折愈合的系统-网络方法可以用来确定导致这一复杂特征的核心因素。骨折愈合的环境变异性将使用甲状旁腺激素（PTH）治疗和磷酸盐缺乏来模拟，前者可以促进愈合，后者可以模拟佝偻病并抑制愈合。骨折愈合中的遗传变异将使用三种具有明显骨质量差异的近交系小鼠进行建模。本研究的第一个目的是建立愈伤组织的特定结构特征、细胞和组织类型与特异性愈伤组织之间的功能关系

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.