Identification of Genes Regulating PTH-Mediated Skeletal Strength

调节 PTH 介导的骨骼强度基因的鉴定

基本信息

批准号：
10682591
负责人：
DOUGLAS J ADAMS
金额：
$ 63万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10682591
关键词：
3-Dimensional Affect Age Alleles American Amino Acids Animal Model Animals Architecture Bayesian Modeling Bone Density Bone Diseases Bone Matrix Bone Tissue Bone remodeling Candidate Disease Gene Chromosome Mapping Clinical Collection Complex Data Diagnosis Disease Dual-Energy X-Ray Absorptiometry Engineering Environment Failure Forteo Fracture Gene Expression Gene Modified Genes Genetic Genetic Predisposition to Disease Genetic study Genome Geometry Goals Health Human Incidence Individual Intervention Investigation Knowledge Length Maps Measures Mechanics Mediating Metabolic Diseases Molecular Monitor Mus Organ Osteogenesis Osteoporosis PTH gene Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Physiology Pilot Projects Population Property Public Health Quantitative Trait Loci Recombinants Regulation Research Design Resistance Resolution Shapes Signal Transduction Structure Study models Testing Tissues Work analog bone bone mass bone strength candidate identification design fracture risk gene interaction genetic makeup improved insight mechanical properties novel parathyroid hormone-related protein phenotypic data response skeletal substantia spongiosa trait transcriptome transcriptome sequencing transcriptomics

项目摘要

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.

骨质疏松症是骨质减少的复杂疾病，影响了所有美国人的一半 50岁，导致骨折。临床上，使用骨矿物质密度（BMD）用于评估断裂风险，但BMD是断裂事件的不完善的预测指标。一个整个骨头是由存在的骨骼，其几何形状和内部建筑所决定的，其结构材料的机械完整性。许多研究确定了许多与骨强度相关的表型性状在遗传上受到控制，但大多数研究没有考虑骨基质的组成。 Teriparatide是第34条的重组形式甲状旁腺赛酮（PTH）的氨基酸是一种临床上建立的骨骼合成代谢疗法。使用BMD变化3％的标准作为对Teriparatide的反应的证据，研究具有表明，经过18个月的治疗后，多达9％的患者没有显示BMD的增加。但是，这些无反应性患者中有77％确实显示出骨形成的强劲增加标记。已经提出，这种反应的多样性可能是由于遗传因素引起的。这该项目的总体目标是确定参与骨骼调节的基因机械完整性，并通过与甲状旁腺激素（PTH）相互作用来做到这一点。在这个应用我们将使用多样性杂种（DO），该杂种是为遗传研究而设计的克服映射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建筑有关。在第一个目的中，我们将扩大表型为包括在组织水平上的机械完整性测试，绘制高分辨率定量性状基因座（QTL）的测试从整个身体骨骼质量到单个骨骼强度，结构和大小，以进行组织水平的机械完整性。作为其中的一部分目的，我们寻求识别与PTH：1-34与间歇性治疗相互作用的基因以影响骨骼。第二个目的，我们将使用DO的8个创始人菌株来研究PTH对骨骼的影响组成及其如何影响骨骼强度。我们将进行基因表达研究以构建基因 - 基因相互作用网络以识别PTH影响骨骼的机制。我们的全面的表型管道将使我们能够识别多个新基因控制骨骼机械完整性，并通过将PTH纳入研究设计：我们还将确定控制骨骼的关键基因，从而是遗传上的“特定于上下文” 它们的遗传差异只有在改变环境时才能揭露。这些基因将帮助我们了解PTH如何影响以前未知的方面。