Bone Structural Integrity Profiling to Advance Skeletal Genetics and Biomechanics

骨结构完整性分析以推进骨骼遗传学和生物力学

• 批准号: 8471655
• 负责人: LORENA M HAVILL
• 金额: $ 63.91万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471655
• 关键词: Adherence; Affect; Age; Area; Behavior; Biological; Biomechanics; Body Size; Bone Density; Bone Tissue; Characteristics; Complex; Computer Simulation; Descriptor; Development; Disease; Environment; Exhibits; Female; Femur; Fracture; Future; Genes; Genetic; Genetic Variation; Goals; H2 gene; Health; Heritability; Individual; Knowledge; Length; Link; Maintenance; Measures; Mechanics; Mediating; Methods; Molecular; Morphology; Musculoskeletal; Osteoporosis; Papio; Pathway Analysis; Pattern; Performance; Population; Principal Component Analysis; Process; Property; Public Health; Research Design; Resistance; Risk; Role; Shapes; Simulate; Speed; Structure; Testing; Therapeutic; Tissues; Variant; Work; age effect; age related; bone; bone quality; bone strength; design; falls; gene discovery; improved; male; sex; skeletal; substantia spongiosa; trait; transcriptome sequencing

DESCRIPTION (provided by applicant): The structural integrity of bone in any mechanical loading environment is an integrative function of a multitude of complex and interrelated characteristics of bone at the macro-, micro- and ultrastructural levels of bone's structural organization. Bone fragility and increased fracture risk result from multiple, distinct combinations of scores of bone traits. A dynamic process of co-adaptation of traits provides for redundant combinations of traits through which structures are produced that provide adequate functionality under "normal" loading conditions. However, some of these combinations of traits can result in structures that are suboptimal when subjected to atypical or traumatic loads, such as those encountered in a fall. The dominant study design in skeletal genetics and biomechanics focuses on the role of one or a limited set of morphological and/or compositional factors in bone fragility. This approach is effective for identifying discrete traits that contribute to bone fracture resistance, but we cannot get a complete picture of the mechanobiological processes underlying fracture risk without a more comprehensive study design that captures variation at each of bone's hierarchical levels, since all of these traits work synergistically to control fracture risk. We propose a multi-disciplinary, integrative approach that is a major departure from traditional approaches to skeletal biomechanics and genetics. Our study is designed to identify composite traits comprising uncorrelated expression patterns of specific measures of bone quality and density that are linked to bone structural performance, to estimate the heritability (h2) of these composite traits, and to prioritize genes and gene networks most likely to affect fracture risk. Specifically, we aim to 1) measure a thorough suite of bone traits in the femurs of 100 pedigreed baboons, then use variable reduction methods to distill the multitude of interrelated, highly correlated traits down to a small set of uncorrelated descriptors of variation in bone morphology and composition. Hypothesis: There is a set of uncorrelated, composite traits that efficiently disentangles the elaborate network of compositional and morphological traits responsible for population-level normal variation in bone biomechanical behavior. 2) Characterize age and sex effects on these composite traits, 3) Assess femoral apparent biomechanical properties under normal and non-habitual loading conditions. Hypothesis: Differential expression of these traits in individuals results in structures that support normal functional musculoskeletal activities, a subset of which perform poorly when loaded in a non-habitual manner. 4) Detect and quantify the proportion of variation in each composite descriptor that is due to the additive effects of genes (h2), and 5) Identify genes and networks that are differentially active in bone tissue from strong for size vs. weak for size femurs. Such fundamental knowledge would allow for development of vastly improved preventative and therapeutic strategies for osteoporosis-related fractures.

描述（由申请人提供）：在任何机械载荷环境中，骨的结构完整性是骨结构组织的宏观、微观和超微结构水平上的多种复杂且相互关联的骨特征的综合功能。骨脆性和骨折风险增加是由骨特征评分的多种不同组合引起的。性状的共适应的动态过程提供了性状的冗余组合，通过该组合产生在“正常”加载条件下提供足够功能的结构。然而，当受到非典型或创伤性载荷时，例如跌倒时，这些特征的某些组合可能导致结构不理想。骨骼遗传学和生物力学的主要研究设计集中在一个或一组有限的形态和/或组成因素在骨脆性中的作用。这种方法是有效的识别离散性状，有助于骨折抵抗力，但我们不能得到一个完整的图片的力学生物学过程的骨折风险没有一个更全面的研究设计，捕捉变化在每个骨的层次结构水平，因为所有这些性状协同工作，以控制骨折风险。我们提出了一个多学科的，综合的方法，是一个重大的背离传统的骨骼生物力学和遗传学的方法。我们的研究旨在确定复合性状，包括与骨结构性能相关的骨质量和密度的特定指标的不相关表达模式，以估计这些复合性状的遗传力（h2），并优先考虑最有可能影响骨折风险的基因和基因网络。具体来说，我们的目标是：1）测量100只纯种狒狒股骨的一整套骨骼特征，然后使用变量缩减方法将大量相互关联、高度相关的特征提取到一小部分骨骼形态和组成变化的不相关描述符。假设：有一组不相关的复合性状，有效地解开了复杂的网络组成和形态特征负责人口水平的正常变化，骨生物力学行为。2)描述年龄和性别对这些复合特征的影响，3）评估股骨在正常和非习惯性载荷条件下的表观生物力学特性。假设：这些特征在个体中的差异表达导致支持正常功能性肌肉骨骼活动的结构，其中一个子集在以非习惯性方式加载时表现不佳。4)检测和量化由于基因的加性效应而导致的每个复合描述符中的变化的比例（h2），以及5）从大小股骨的强与大小股骨的弱来识别在骨组织中差异活性的基因和网络。这些基础知识将允许开发出大大改进的预防和治疗策略，用于与骨关节炎相关的骨折。