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理解表型共变异如何促进骨骼脆弱性的遗传基础。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，形成了成体特征。此外，这些功能关系与当前基于菌株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弱性的决定性因素。我们假设表型共变是一种遗传决定的性状，它同时协调骨骼生物学的基本方面，以匹配发育过程中的负荷需求。我们建议利用C57BL/6J-ChrA/J染色体替代菌株（CSSs），通过定位改变表型共变（Aim 1）的数量性状位点（qtl）来验证这一假设。此外，我们假设改变表型共变的等位基因变异是由于对机械负荷的响应性改变所致。我们通过确定调节表型共变异和运动适应性反应的qtl是否映射到相同的基因组区域来验证这一假设（Aims 2,3）。发现这种关联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每个层次的结构层次，以便为qtl分配生物学功能。为了做到这一点，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将显示出特定性状或特定性状相互作用的改变，这可能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，在生长过程中作为协调细胞活动的共同控制（即功能适应）。我们将重点关注GH/IGF轴，因为这是产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相互作用的新qtl，而且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见解。

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.