Systems Genetics of Osteoblast Activity

成骨细胞活性的系统遗传学

• 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
• 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

 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丢失的疾病，导致骨骼脆弱和容易骨折。这种疾病影响了大约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，具有与骨折相关的特征，如骨密度(BMD)，是最易遗传的疾病相关表型之一。到目前为止，在人类和老鼠身上，遗传学研究几乎完全集中在骨密度的分析上。然而，BMD是一个复杂的组织水平的特征，受到复杂的遗传和环境因素的影响。这阻碍了我们准确识别构成遗传关联的因果基因的能力。作为另一种选择，我们建议只专注于一种更简单的细胞水平过程的遗传学，即成骨细胞介导的骨形成。这项建议的目的是确定影响成骨细胞功能的基因。这将使用一种名为协作交叉(CC)的新颖和创新的小鼠遗传参考种群来实现。在一项先导性研究中，我们确定了小鼠成骨细胞活动的两个基因组范围的关联，并利用骨表达和人类GWA确定了三个可能存在这些关联的候选基因。在目标1中，我们将在体外评估这些候选基因表达水平的调节对成骨细胞功能的影响。在目标2中，我们将定位CC中矿化结节形成的额外高分辨率数量性状基因座(QTL)，矿化结节形成是成骨细胞介导的骨形成的生理相关指标。在目标3中，我们将从QTL转移到矿化结核形成QTL候选基因的识别和验证。这将通过利用CC的独特遗传方面来从生物信息上缩小这些基因座的范围，随后进行RNA-seq/Expression QTL研究以进一步精确定位致病基因。矿化结核形成QTL的候选基因将通过基因过表达、基因敲除和突变小鼠研究进行测试。我们期望，对细胞水平过程的研究将提供更有效地从位点到基因再到机制的手段。我们确定的基因将作为潜在的治疗靶点，能够在骨质疏松症的背景下增加骨形成。