Systems Genetics of Osteoblast Activity

成骨细胞活性的系统遗传学

基本信息

批准号：
8743076
负责人：
Cheryl Lynne Ackert-Bicknell
金额：
$ 33.13万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-27 至 2015-09-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8743076
关键词：
Affect Age American Anabolic Agents Area Biology Bone Density Bone Development Bone Resorption Calvaria Candidate Disease Gene Cells Complex Data Development Disease Dissection Drug Targeting Economic Burden Ensure Environmental Risk Factor Fracture Genes Genetic Goals Hereditary Disease Heritability Human In Vitro Individual Laboratories Lead Maps Measures Mediating Medical Economics Methodology Mus Nodule Osteoblasts Osteoclasts Osteogenesis Osteoporosis Phenotype Pilot Projects Population Process Progressive Disease Public Health Quantitative Trait Loci Regulation Research Resolution Risk Societies System Testing Therapeutic Time Translating Validation WNT4 gene base bone bone loss bone mass bone strength clinically relevant common treatment design gene discovery genetic analysis genetic association genome wide association study in vivo innovation knock-down mouse genome new therapeutic target novel osteoporosis with pathological fracture overexpression public health relevance success therapeutic target trait transcriptome sequencing transcriptomics

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 American society. Osteoporosis is primarily a genetic disorder with fracture predicting 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 almost exclusively focused 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, and more importantly, their mechanisms of action, 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 a genetic locus on mouse Chr 4 for osteoblast-mediated bone formation using genome-wide association mapping and determined that Wnt4 was the candidate gene for this locus. In Aim 1, we will evaluate the effect of modulating expression levels of Wnt4 on osteoblast function in vitro and the effects of deleting Wnt4 on bone mass and strength in vivo. 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 of 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 pin point causative genes. Candidate genes for mineralized nodule formation QTL will be tested by gene overexpression and knockdown 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. Wnt4 and additional genes that will be identified 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，导致易于骨折的骨骼易于骨骼。这种疾病影响了约1200万美国人，是美国社会的主要医学和经济负担。骨质疏松症主要是一种遗传疾病，其骨折预测性状，例如骨矿物质密度（BMD），是与疾病相关的表型中最高度遗传的疾病之一。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是一种复杂的生物水平特征，受遗传和环境因素的复杂环境的影响。这阻碍了我们精确识别因果基因的能力，更重要的是，它们的作用机理是遗传关联的基础。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，我们使用全基因组缔合映射确定了成骨细胞介导的骨形成的小鼠ChR 4的遗传基因座，并确定Wnt4是该基因座的候选基因。在AIM 1中，我们将评估调节Wnt4表达水平对体外成骨细胞功能的影响以及删除Wnt4对骨骼质量和体内强度的影响。在AIM 2中，我们将绘制其他高分辨率定量性状基因座（QTL）的矿化结节形成，这是CC中成骨细胞介导的骨骼形成的生理相关度量。在AIM 3中，我们将从QTL转移到矿化结节形成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来生物信息上缩小这些基因座的范围，然后进行RNA-Seq/表达QTL研究，以进一步的PIN点致病基因。矿化结节形成QTL的候选基因将通过基因过表达和敲低研究测试。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。 WNT4和将被鉴定出的其他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。