Systems Genetics of Osteoblast Activity

成骨细胞活性的系统遗传学

基本信息

批准号：
9294972
负责人：
Cheryl Lynne Ackert-Bicknell
金额：
$ 40.19万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-21 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294972
关键词：
Affect Age Alpha Cell American Anabolic Agents Area BTB/POZ Domain Bioinformatics Biology Bone Density Bone Development Bone Diseases Bone Resorption Calvaria Candidate Disease Gene Cells Complex Data Development Disease Dissection Drug Targeting Economic Burden Ensure Environmental Risk Factor Fracture Genes Genetic Genetic study Goals Hereditary Disease Heritability Human Human Genetics Human Genome In Vitro Individual Laboratories Lead Maps Measures Mediating Medical Economics Methodology Minerals Mus Mutant Strains Mice Nodule Osteoblasts Osteoclasts Osteogenesis Osteoporosis Phenotype Physiological Pilot Projects Population Process Progressive Disease Protein Kinase Proteins Public Health Quantitative Trait Loci Regulation Research Resolution Risk Role Societies System Testing Therapeutic Time WNT4 gene Zinc Fingers base bone bone mass candidate validation common treatment fracture risk gene discovery genetic analysis genetic association genome wide association study genome-wide in vivo innovation knock-down new therapeutic target novel novel strategies osteoporosis with pathological fracture overexpression public health relevance success therapeutic target trait transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant) Osteoporosis is a disease of progressive bone loss, leading to weak and fracture prone bones. This disease affects ~12 million Americans and is a major medical and economic burden on society. Osteoporosis is primarily a genetic disorder with fracture-related traits, such as bone mineral density (BMD), being among the most highly heritable disease associated phenotypes. In humans and mice, genetic studies to date have focused almost exclusively on the analysis of BMD. However, BMD is a complex organismal-level trait that is influenced by a complicated milieu of genetic and environmental factors. This has hampered our ability to precisely identify the causal genes that underlie genetic associations. As an alternative, we propose to focus exclusively on the genetics of a more 'simple' cell-level process, osteoblast-mediated bone formation. The objective of this proposal is to identify genes affecting osteoblast function. This will be accomplished using a novel and innovative mouse genetic reference population termed the Collaborative Cross (CC). In a pilot study, we identified two genome-wide associations in the mouse for osteoblast activity and using bone expression and human GWAS we have identified three candidate genes potentially underlying these associations. In Aim 1, we will evaluate the effect of modulating expression levels of these candidates on osteoblast function in vitro. In Aim 2, we will map additional high-resolution quantitative trait loci (QTL) for mineralized nodule formation, a physiologically relevant measure of osteoblast-mediated bone formation, in the CC. In Aim 3, we will move from QTL to the identification and validation of candidate genes for mineralized nodule formation QTL. This will be accomplished by exploiting the unique genetic aspects of the CC to bioinformatically narrow these loci, followed by RNA-seq/expression QTL studies to further pinpoint causative genes. Candidate genes for mineralized nodule formation QTL will be tested by gene overexpression and knockdown and mutant mouse studies. We expect that the study of a cell-level process will provide the means to more efficiently go from locus to gene to mechanism. Genes that we identify will serve as potential therapeutic targets capable of increasing bone formation in the setting of osteoporosis.

描述（由申请人提供）骨质疏松症是一种进行性骨质流失的疾病，导致易于骨折和骨折。这种疾病影响了约1200万美国人，是社会的主要医学和经济焚烧。骨质疏松症是一种遗传疾病，具有与骨折相关性状的特征，例如骨矿物质密度（BMD），是最高度遗传性疾病相关的表型之一。在人类和小鼠中，迄今为止的遗传研究几乎完全集中在BMD的分析上。但是，BMD是一个复杂的有机特征，受遗传和环境因素的复杂环境的影响。这阻碍了我们准确识别遗传关联构成的毒素基因的能力。作为替代方案，我们建议将更简单的细胞水平过程，成骨细胞介导的骨形成的遗传学专注。该建议的目的是确定影响成骨细胞功能的基因。这将使用称为协作交叉（CC）的新颖而创新的小鼠遗传参考人群来实现。在一项试点研究中，我们确定了小鼠中的两个全基因组关联，用于成骨细胞活性，并使用骨骼表达和人类GWA，我们已经确定了可能潜在的这些关联潜在的三个候选基因。在AIM 1中，我们将评估这些候选者在体外调节成骨细胞功能的表达水平的影响。在AIM 2中，我们将在CC中绘制其他高分辨率定量性状位置（QTL）的矿化节点形成，这是成骨细胞介导的骨形成的物理相关度量。在AIM 3中，我们将从QTL转到矿化节点形成QTL的候选基因的识别和验证。这将通过利用CC的独特遗传方面来实现这一目标，从而生物信息上缩小了这些位置，然后进行RNA-Seq/表达QTL研究以进一步查明严重的基因。矿化结节形成QTL的候选基因将通过基因过表达和敲低和突变小鼠研究来测试。我们期望对细胞水平过程的研究将提供从基因座到基因到机制更有效地进行的手段。我们确定的基因将作为能够在骨质疏松症的情况下增加骨形成的潜在治疗靶标。