Identification of Genes Regulating PTH-Mediated Skeletal Strength

调节 PTH 介导的骨骼强度基因的鉴定

• 批准号: 10226155
• 负责人: DOUGLAS J ADAMS
• 金额: $ 63.82万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/10226155
• 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; design; fracture risk; gene interaction; genetic makeup; genomic locus; improved; insight; mechanical properties; novel; parathyroid hormone-related protein; phenotypic data; response; skeletal; substantia spongiosa; trait; transcriptome; transcriptome sequencing; transcriptomics

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.

骨质疏松症是一种骨量减少的复杂疾病，影响着一半以上的美国人 50 岁并导致衰弱性骨折，临床上使用骨矿物质密度 (BMD)。 用于评估骨折风险，但 BMD 并不能完全预测骨折发生率。 整个骨骼由存在的骨骼数量、其几何形状和内部结构以及 大量研究已证实其结构材料的机械完整性。 与骨强度相关的表型特征是由基因控制的，但大多数研究 没有考虑骨基质的成分，特立帕肽是前34的重组形式。 甲状旁腺激素 (PTH) 的氨基酸，是临床上建立的骨合成代谢疗法。 研究使用 BMD 变化 3% 的标准作为对特立帕肽有反应的证据 研究表明，高达 9% 的患者在治疗 18 个月后 BMD 没有增加。 然而，77% 的无反应患者确实表现出骨形成的强劲增加 有人认为这种反应的多样性可能是由于遗传因素造成的。 该项目的总体目标是确定参与骨调节的基因 机械完整性，通过与甲状旁腺激素 (PTH) 的相互作用来实现。 应用程序中，我们将使用 Diversity Outbred (DO)，它是为遗传研究而设计的 在使用 DO 的试点研究中，我们克服了作图分辨率和表型多样性的问题。 表明我们可以识别候选基因，而不仅仅是基因组内的区域 与骨骼大小和结构相关。在第一个目标中，我们将扩展我们的表型分析以包括。 组织水平的机械完整性测试，绘制高分辨率数量性状基因座（QTL） 一系列互补性状，其长度范围从全身骨骼质量到 个体骨骼强度、结构和尺寸，以达到组织水平的机械完整性。 我们的目标是寻找与 PTH:1-34 间歇性治疗相互作用以影响骨骼的基因。 第二个目标，我们将使用DO的8个创始菌株来研究PTH对骨骼的影响 我们将进行基因表达研究来构建。 基因-基因相互作用网络，以确定 PTH 影响骨骼的机制。 全面的表型分析流程将使我们能够识别多个新基因，这些基因有助于 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“特定于环境的” 只有当环境存在时，它们的遗传差异才会被暴露出来。这些基因会帮助我们做到这一点。 了解 PTH 如何在以前未知的方面影响骨骼。