A Systems Genetics Approach to Fracture Healing

骨折愈合的系统遗传学方法

• 批准号: 8894407
• 负责人: Louis Charles Gerstenfeld
• 金额: $ 36.83万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894407
• 关键词: Address; Affect; Aging; Area; Bioinformatics; Biological; Biological Markers; Biological Process; Biomechanics; Bone Development; Bone Regeneration; Bone callus; Cells; Clinical; Clinical Management; Comparative Study; Competence; Complex; Computing Methodologies; Data; Dependency; Development; Diagnostic; Elements; Environmental Risk Factor; Fracture; Fracture Healing; Gene Cluster; Genes; Genetic; Genomics; Goals; Healed; Health; Healthcare; Histocompatibility Testing; Homeostasis; Hormones; Human; Inbred Strains Mice; Individual; Injury; Knowledge; Maps; Mechanics; Metabolism; Minerals; Modeling; Molecular; Molecular Target; Ontology; Organ; Osteoporosis; Parathyroid gland; Pathology; Pathway interactions; Plant Roots; Process; Property; Regression Analysis; Regulation; Regulatory Pathway; Rickets; Signal Transduction Pathway; Site; Structure; System; Testing; Therapeutic Intervention; Time; Tissues; Weight-Bearing state; Work; X-Ray Computed Tomography; bone quality; cell type; differential expression; genetic approach; healing; improved; indexing; innovation; inorganic phosphate; novel therapeutics; prognostic; repaired; research study; response; trait; transcription factor

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.

描述（由申请人提供）：骨折是最常见的大器官外伤之一，而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。骨折愈合可以被认为是一种复杂的特征，其定义为允许恢复负重的机械能力的恢复。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。许多个体表型特性，例如矿化组织的数量和愈伤组织的结构，促成了这种复杂的性状，并且每个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，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，从而确定促成这一复杂特征的核心要素。骨折愈合的环境变异性将使用甲状旁腺激素（PTH）治疗（可促进愈合）和磷酸盐缺乏（模拟佝偻病并抑制愈合）进行建模。骨折愈合的遗传变异性将使用三种近交系小鼠进行建模，这些小鼠具有明显的骨质量差异。拟议工作的第一个目标是建立愈伤组织、细胞和组织类型的特定结构特征以及特定的功能之间的功能关系。 有助于骨折骨机械性能恢复速度的生物过程。这将通过组织学分析、显微计算机断层扫描和生物力学测试来实现，以量化器官、组织和细胞水平上骨折愈伤组织表型特性的时间变化。然后，将使用多元回归分析和路径分析来确定各种表型特性之间的功能依赖性以及它们与恢复强度的关系。第二个目标是确定有助于骨折愈合的差异表达基因作为一种特征。全局转录分析和多种生物信息学方法将用于定义在骨折愈合过程中以及响应遗传变异和环境扰动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。将鉴定差异表达基因组与各种表型特性之间的因果关系，并将用于定义控制这些表型特性的分子功能。总的来说，这些研究将确定临床上可用于评估愈合的相关因素和促进愈合的分子靶点。