Systems Genetics of Osteoblast Activity

 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，导致骨骼脆弱和容易骨折。这种疾病影响约1200万美国人，是社会的主要医疗和经济负担。骨质疏松症主要是一种遗传性疾病，具有骨相关性状，如骨矿物质密度（BMD），是最高度遗传的疾病相关表型之一。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。然而，BMD是一种复杂的生物体水平特征，受遗传和环境因素的复杂环境影响。这阻碍了我们精确识别遗传关联背后的因果基因的能力。作为一种替代方案，我们建议专注于一个更简单的细胞水平的过程，成骨细胞介导的骨形成的遗传学。这个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）的新型和创新的小鼠遗传参考群体来完成。在一项初步研究中，我们确定了小鼠成骨细胞活性的两个全基因组关联，并使用骨表达和人类GWAS，我们确定了三个潜在的候选基因。在目的1中，我们将评估调节这些候选物的表达水平对体外成骨细胞功能的影响。在目标2中，我们将绘制额外的高分辨率的数量性状位点（QTL）矿化结节形成，成骨细胞介导的骨形成的生理相关措施，在CC。在目标3中，我们将从QTL转移到矿化结节形成QTL的候选基因的鉴定和验证。这将通过利用CC的独特遗传方面来实现，以在生物信息学上缩小这些基因座，然后进行RNA-seq/表达QTL研究以进一步查明致病基因。矿化结节形成QTL的候选基因将通过基因过表达和敲低以及突变小鼠研究进行测试。我们希望对细胞水平过程的研究将提供更有效地从基因座到基因再到机制的方法。我们发现的基因将作为潜在的治疗靶点，能够增加骨质疏松症的骨形成。

 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.