Identification of Genes Regulating PTH-Mediated Skeletal Strength

骨质疏松症是一种骨质减少的复杂疾病， 50岁，导致衰弱性骨折。临床上，骨矿物质密度（BMD） 但骨密度不能完全预测骨折发生率。的实力 整个骨骼取决于存在的骨骼量、其几何形状和内部结构， 其结构材料的机械完整性。大量研究表明，许多 与骨强度相关的表型性状受遗传控制，但大多数这些研究 没有考虑骨基质的组成。特立帕曲肽是前34种 甲状旁腺激素（PTH）的氨基酸，是临床上确立的骨合成代谢疗法。 使用BMD变化3%的标准作为对特立帕鲁肽反应的证据，研究表明， 结果显示，高达9%的患者在治疗18个月后BMD没有增加。 然而，这些无反应的患者中有77%确实显示出骨形成的强劲增长 标记。有人认为，这种反应的多样性可能是由于遗传因素造成的。的 该项目的总体目标是确定参与骨调节的基因， 机械完整性，并且其通过与甲状旁腺激素（PTH）的相互作用来实现。在这 应用程序，我们将使用多样性远交（DO），这是专为遗传研究， 克服作图分辨率和表型多样性的问题。在使用DO的试点研究中，我们 表明我们可以识别候选基因，而不仅仅是基因组中的区域， 与骨骼大小和结构相关。在第一个目标中，我们将扩大我们的表型，包括 组织水平的机械完整性测试，绘制高分辨率的数量性状基因座（QTL）， 一组互补的特征，长度范围从全身骨骼质量到 个体骨强度、结构和尺寸与组织水平机械完整性之间的关系。作为其中的一部分 我们的目的是寻找与PTH：1-34间歇治疗相互作用的基因，以影响骨骼。在 第二个目的，我们将使用DO的8个创始菌株来研究PTH对骨的影响 以及它如何影响骨骼强度。我们将进行基因表达研究， 基因-基因相互作用网络，以确定PTH影响骨骼的机制。我们 全面的表型分析管道将使我们能够识别多个新的基因， 控制骨机械完整性，并将PTH：1-34治疗纳入研究设计 我们还将确定控制骨骼的关键基因，这些基因在遗传上是“环境特异性的”， 只有当环境改变时，它们的遗传差异才会显露出来。这些基因将帮助我们 了解PTH如何在以前未知的方面影响骨骼。

Osteoporosis is a complex disease of decreased bone mass that impacts half of all Americans over the age of 50 and results in debilitating bone fracture. Clinically, bone mineral density (BMD) is used for assessing fracture risk, but BMD is an imperfect predictor of fracture incidence. The strength of a whole bone is dictated by the amount of bone present, its geometry and internal architecture, and the mechanical integrity of its structural material. Numerous studies have established that many phenotypic traits associated with bone strength are controlled genetically, but most of these studies did not consider the composition of the bone matrix. Teriparatide is a recombinant form of the first 34 amino acids of parathyroid hormone (PTH) and is a clinically established anabolic therapy for bone. Using the criterion of a 3% change in BMD as evidence of response to Teriparatide, studies have shown that up to 9% of patients do not show an increase in BMD after 18 months of treatment. However, 77% of these non-responsive patients did show a robust increase in bone formation markers. It has been suggested that this diversity in response may be due to genetic factors. The overall goal of this project is to identify genes that participate in the regulation of bone mechanical integrity, and which do so via interaction with parathyroid hormone (PTH). In this application we will be using the Diversity Outbred (DO), which was designed for genetic studies to overcome issues of mapping resolution and phenotypic diversity. In a pilot study using the DO, we showed that we can identify candidate genes, rather than just regions within the genome, that are associated with bone size and architecture. In the first Aim, we will expand our phenotyping to include tests of mechanical integrity at the tissue level, mapping high-resolution quantitative trait loci (QTL) for a collection of complementary traits ranging in length scale from whole body skeletal mass to individual bone strength, architecture, and size, to tissue-level mechanical integrity. As part of this aim, we seek identify genes that interact with intermittent treatment with PTH:1-34 to impact bone. In the second Aim, we will use the 8 founder strains of the DO to study the impact of PTH on bone composition and how that impacts bone strength. We will conduct gene expression studies to build gene-gene interaction networks to identify mechanisms by which PTH impacts bone. Our comprehensive phenotyping pipeline will allow us to identify multiple new genes instrumental for controlling bone mechanical integrity, and that by incorporating PTH:1-34 treatment into study design we will additionally identify key genes controlling bone that genetically are “context specific” in that their genetic differences are only unmasked when environment is altered. These genes will help us to understand how PTH impacts bone in aspects not previously known.