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.

骨质疏松症是一种复杂的骨量减少的疾病，影响超过一半的美国人 50岁，导致虚弱的骨折。在临床上，使用骨密度(BMD) 用于评估骨折风险，但骨密度不是骨折发生率的完美预测指标。一家公司的实力 整个骨骼由存在的骨骼的数量、其几何形状和内部结构以及 其结构材料的机械完整性。大量研究已经证实，许多 与骨骼强度相关的表型特征是由基因控制的，但这些研究中的大多数 没有考虑骨基质的组成。Teriparatide是一种重组形式的前34 甲状旁腺激素(PTH)的氨基酸，是一种临床确立的骨合成代谢疗法。 使用骨密度变化3%的标准作为对特瑞帕坦有效的证据，研究已经 结果显示，高达9%的患者在治疗18个月后骨密度没有增加。 然而，77%的无反应患者确实显示出骨形成的强劲增加。 记号笔。有人认为，这种反应的多样性可能是由于遗传因素造成的。这个 这个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)的相互作用来实现这一点。在这 我们将使用DO(DO)，这是为遗传学研究而设计的 克服图谱分辨率和表型多样性的问题。在一项使用DO的先导研究中，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，即 与骨骼大小和建筑有关。在第一个目标中，我们将扩大我们的表型鉴定，以包括 在组织水平上进行机械完整性测试，绘制高分辨率数量性状基因座(QTL) 从全身骨骼质量到长度尺度的一系列互补性状 个体骨骼强度、结构和大小，到组织级别的机械完整性。作为这项工作的一部分 目的：我们寻找与甲状旁腺素：1-34间歇治疗相互作用的基因，以影响骨骼。在……里面 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 以及它对骨骼强度的影响。我们将进行基因表达研究，以建立 基因-基因相互作用网络，以确定甲状旁腺激素影响骨骼的机制。我们的 全面的表型鉴定流水线将使我们能够识别多个有助于 控制骨机械完整性，并将PTH：1-34治疗纳入研究设计 此外，我们还将确定控制骨骼的关键基因，这些基因在遗传上是“特定于背景的” 只有当环境改变时，它们的遗传差异才会暴露出来。这些基因将帮助我们 了解甲状旁腺激素如何在以前未知的方面影响骨骼。