Functionality and Fracture Susceptibility of Corticocancellous Structures

描述（由申请人提供）：骨是一个复杂的系统，其关键功能是足够坚硬和坚固，以支持与日常活动相关的体力。了解遗传和环境变异如何损害这一功能对于充分理解为什么某些人更容易骨折至关重要。骨小梁和皮质特征都有助于皮质松质骨结构的承载，这两种组织类型的相对比例的变化是骨折风险的关键决定因素。然而，个体间皮质和小梁组织相对比例变化的原因还不清楚。基于我们自己的工作，研究小鼠和人类长骨的功能关系，我们假设皮质和骨小梁性状的变化来自功能适应（沃尔夫定律）和影响骨骼大小的遗传变异之间的相互作用。我们建议，以确定如何影响椎体大小的遗传变异，骨折风险的一个关键决定因素，是由皮质和骨小梁性状之间的特定功能相互作用补偿。我们假设，骨小梁的质量和结构的遗传变异取决于遗传变异影响皮质骨的大小和质量所产生的负荷分担程度。此外，我们建议确定皮质和小梁性状之间的功能相互作用如何保持强度与老化。由于表型协变会导致成人性状的遗传变化，我们还检验了某些成人性状集对骨质流失的抵抗力更强，并且随着年龄的增长能够更好地保持力量的假设。我们将使用一组AXB/BXA重组近交（RI）小鼠品系来测试这些假设，这是研究正常（即，非病理性）遗传变异性的范围。在目标I中，我们使用路径分析来测试骨小梁和皮质性状是否表现出补偿关系，并确定补偿影响成人椎体大小的遗传变异的性状相互作用。在目标II中，我们确定了生长过程中表型协变是如何产生的。在目的III中，我们评估了表型协变对骨细胞随着年龄增长保持刚度和强度的能力的影响。最后，我们测试性别如何影响整个生长和衰老的表型协变。这种系统分析，它检查性状之间的关系，在功能的背景下，将提供新的见解骨折易感性的遗传基础。公共卫生相关性：我们建议确定皮质和骨小梁性状之间的功能相互作用如何补偿影响椎体大小的遗传变异，并有助于骨折易感性。我们使用遗传随机化的近交系小鼠品系，以确定如何补偿性状的相互作用，在生长过程中产生的成年性状表达不同的能力，以保持与老化的力量不同的集合。这种系统分析，它检查性状之间的关系，在功能的背景下，将提供新的见解骨折易感性的遗传基础。

DESCRIPTION (provided by applicant): Bone is a complex system whose critical function is to be sufficiently stiff and strong to support the physical forces associated with daily activities. Understanding how genetic and environmental variants compromise this function is critical to fully understanding why certain individuals are more susceptible to fracturing. Trabecular and cortical traits both contribute to load bearing of corticocancellous structures, and variation in the relative proportion of these two tissue types is a critical determinant of fracture risk. However, the cause of variation in the relative proportion of cortical and trabecular tissues among individuals is not well understood. Based on our own work examining functional relationships in mouse and human long bone, we postulate that variation in cortical and trabecular traits arises from an interplay between functional adaptation (Wolff's Law) and genetic variants affecting bone size. We propose to determine how genetic variants affecting vertebral size, a critical determinant of fracture risk, are compensated by specific functional interactions among cortical and trabecular traits. We hypothesize that genetic variation in trabecular bone mass and architecture depends on the degree of load sharing arising from genetic variants affecting cortical size and quality. Further, we propose to determine how the functional interactions among cortical and trabecular traits maintain strength with aging. Because phenotypic covariation gives rise to genetically varying sets of adult traits, we also test the hypothesis that certain adult trait sets will be more resistant to bone loss and better able to maintain strength with aging. We will test these hypotheses using a panel of AXB/BXA Recombinant Inbred (RI) Mouse Strains, which is a powerful model to study compensatory relationships among traits within the normal (i.e., non-pathological) range of genetic variability. In Aim I, we use Path Analysis to test whether trabecular and cortical traits show a compensatory relationship, and identify the trait interactions that compensate for genetic variants affecting adult vertebral size. In Aim II, we determine how phenotypic covariation arises during growth. In Aim III, we assess the impact of phenotypic covariation on the ability of bone cells to maintain stiffness and strength with aging. Finally, we test how sex affects phenotypic covariation throughout growth and aging. This systems analysis, which examines the relationship among traits in the context of functionality, will provide new insight into the genetic basis of fracture susceptibility. PUBLIC HEALTH RELEVANCE: We propose to determine how functional interactions among cortical and trabecular traits compensate for genetic variants affecting vertebral size and contribute to fracture susceptibility. We use genetically randomized inbred mouse strains to determine how compensatory trait interactions arising during growth lead to varying sets of adult traits expressing different abilities to maintain strength with aging. This systems analysis, which examines the relationship among traits in the context of functionality, will provide new insight into the genetic basis of fracture susceptibility.