Bone Structural Integrity Profiling to Advance Skeletal Genetics and Biomechanics

描述(申请人提供)：骨在任何机械载荷环境中的结构完整性是骨的结构组织的宏观、微观和超微结构水平上的多种复杂和相互关联的特征的综合作用。骨骼的脆性和骨折风险的增加是多种不同的骨骼特征组合的结果。性状共同适应的动态过程提供了冗余的性状组合，通过这些组合产生的结构在“正常”负荷条件下提供了足够的功能。然而，这些特征的一些组合可能会导致结构在承受非典型或创伤性负荷时不是最理想的，比如在跌倒时遇到的那些。在骨骼遗传学和生物力学中占主导地位的研究设计侧重于一种或一组有限的形态和/或成分因素在骨脆性中的作用。这种方法对于确定影响骨折抗力的离散特征是有效的，但如果没有一个更全面的研究设计来捕捉每个骨骼等级水平的差异，我们就不能完整地了解潜在骨折风险的机械生物学过程，因为所有这些特征都协同作用来控制骨折风险。我们提出了一种多学科的综合方法，这是对骨骼生物力学和遗传学的传统方法的重大偏离。我们的研究旨在确定包含骨质量和密度的特定测量与骨结构性能相关的不相关表达模式的复合性状，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。具体地说，我们的目标是：1)测量100只纯种狒狒股骨的一套完整的骨骼特征，然后使用变量约简方法提取大量相互关联、高度相关的特征，最终得到一小部分不相关的骨骼形态和成分变异描述符。假设：存在一组不相关的复合性状，它们有效地解开了复杂的组成和形态特征网络，这些特征是导致骨生物力学行为在种群水平上正常变化的原因。2)表征年龄和性别对这些综合特征的影响；3)评估正常和非习惯性负荷条件下股骨的表观生物力学特性。假设：这些特征在个体中的不同表达导致了支持正常功能肌肉骨骼活动的结构，其中一部分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(H2)的相加效应而导致的每个复合描述符中的变异比例，以及5)识别在骨组织中不同地活跃的基因和网络，这些基因和网络对于大小的股骨来说是强的还是弱的。这些基础知识将使我们能够极大地改进骨质疏松症相关骨折的预防和治疗策略。

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.