Genetic Determination of Skeletal Fragility

描述(由申请人提供)：我们竞争更新的目标是更好地了解表型协变如何有助于骨骼脆性的遗传基础。初步研究表明，在出生后的生长过程中，通过基质矿化和骨表面扩张之间的功能相互作用，形成了一系列成体特征。此外，这些功能关系与当前基于应变的生物反馈系统如何运作的理论一致，是成人骨骼功能和脆性的决定性因素。我们假设，表型协变是一种遗传决定的特征，它同时协调骨生物学的基本方面，以匹配发育过程中的负荷需求。我们建议通过使用C57BL/6J-Chra/J染色体替代品系(CSS)来定位改变表型协变(目标1)的数量性状座位(QTL)来检验这一假设。此外，我们假设改变表型协变的等位基因变异是由于对机械负荷的反应改变所致。我们通过确定调控表型协变和运动适应性反应的QTL是否映射到相同的基因组区域(目标2，3)来检验这一假设。发现这种联系将意味着骨骼生长模式可以用来预测骨骼对机械负荷的反应。最后，我们建议系统地评估结构层次的每个水平，以便将生物学功能分配给QTL。为了实现这一目标，我们将QTL分析与细胞活性和血清生长因子的定量分析相结合。许多CSS会表现出特定性状或特定性状交互作用的变化，预计这与生长过程中内分泌信号的可测量变化有关。因此，这种遗传扰动实验使我们能够寻找一种生物因素，作为协调生长过程中细胞活动的共同控制因素(即功能适应)。我们将重点关注生长激素/胰岛素样生长因子轴，因为这是出生后生长的主要决定因素。这些研究不仅将确定在生长过程中调节性状交互作用的新QTL，而且结果还将为功能适应如何缓冲导致细长骨表型的遗传变异的有害机械后果提供重要的见解。 公共卫生相关性：生长一个健壮的、抗骨折的骨骼是许多降低骨折风险策略的主要目标。通过使用一种将遗传变异与骨骼生长模式和机械功能联系起来的系统方法，我们建议对生长过程中的遗传变异如何导致增加骨折易感性的“危险成人特征集”有新的理解。

DESCRIPTION (provided by applicant): Our goal for the competing renewal is to better understand how phenotypic covariation contributes to the genetic basis of skeletal fragility. Preliminary studies indicate that sets of adult traits are established during post-natal growth through functional interactions between matrix mineralization and bone surface expansions. Further, these functional relationships, which were consistent with current theories of how a strain-based biological feedback system operates, were deterministic of adult bone functionality and fragility. We hypothesize that phenotypic covariation is a genetically determined trait that simultaneously coordinates essential aspects of bone biology to match loading demands during development. We propose to test this hypothesis by mapping quantitative trait loci (QTLs) that alter phenotypic covariation (Aim 1) using C57BL/6J-ChrA/J Chromosome Substitution Strains (CSSs). Further, we hypothesize that allelic variants that alter phenotypic covariation result from an altered responsiveness to mechanical loading. We test this hypothesis by determining whether QTLs regulating phenotypic covariation and the adaptive response to exercise map to the same genomic regions (Aims 2, 3). Finding this association would mean that skeletal growth patterns could be used as a predictor of the responsiveness of bone to mechanical loading. Finally, we propose to systematically assess each level of structural hierarchy in order to assign biological functionality to the QTLs. To accomplish this, we combine QTL analyses with quantitative analyses of cellular activity and serum growth factors. Many CSSs will show alterations in a specific trait or a specific trait interaction, and this is expected to be associated with measurable changes in endocrine signals during growth. This genetic perturbation experiment thus allows us to seek a biological factor that acts as a common control coordinating cellular activities during growth (i.e., functional adaptation). We will focus on the GH/IGF axis since this is the primary determinant of post-natal growth. These studies will not only identify novel QTLs regulating trait interactions during growth, but the results should also provide important insight into how functional adaptation buffers the deleterious mechanical consequences of genetic variants leading to slender bone phenotypes. PUBLIC HEALTH RELEVANCE: Growing a robust, fracture-resistant skeleton is a major goal for many fracture risk reduction strategies. By using a systems approach relating genetic variants to patterns of skeletal growth and to mechanical function, we propose to gain a new understanding of how genetic variation in growth leads to "at-risk sets of adult traits" that increase fracture susceptibility.