IDENTIFYING POLYMORPHISMS IN THE LRP5 GENE IN BABOONS

鉴定狒狒 LRP5 基因的多态性

• 批准号: 7716122
• 负责人: LORENA M HAVILL
• 金额: $ 0.04万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716122
• 关键词: 11q12; Affect; Animals; Area; Bone Density; Chromosomes; Computer Retrieval of Information on Scientific Projects Database; Data; Disease; Exons; Funding; Future; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Grant; Human; Human Genetics; Inbred Mouse; Institution; Investigation; LDL-Receptor Related Protein 1; Maintenance; Metabolism; Modeling; Mus; Mutation; Numbers; Osteoporosis; Papio; Phylogenetic Analysis; Physiology; Population; Primates; Research; Research Personnel; Resources; Sampling; Single Nucleotide Polymorphism; Skeletal system; Source; Study models; United States National Institutes of Health; Variant; bone; bone quality; lipoprotein receptor related protein 5; skeletal disorder

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mutations in the Low-density-lipoprotein-receptor-related protein 5 (Lrp5) in humans are responsible for skeletal disorders of both high and low bone mineral density (BMD). Inbred mouse studies have confirmed the effect of Lrp5 mutations on several aspects of bone quality. The extent to which variation in the Lrp5 gene contributes to normal variation in bone mineral density (BMD) in the general human population is currently the subject of intense investigation because of the large numbers of people affected by bone fragility diseases such as osteoporosis. Recent studies suggest that Lrp5 polymorphisms may indeed contribute to population level BMD variation. Mouse studies are serving to identify potential mechanisms of Lrp5 influence on bone, but extrapolation to humans of results from studies of such distantly related species can be problematic. The phylogenetic proximity of the baboon to humans and consequent similarities in skeletal physiology and metabolism make it an excellent model for studies of the genetics of human skeletal maintenance. A previous study shows significant evidence for a gene on chromosome 11q12-13 (the area of Lrp5) that affects normal variation in BMD in the baboon. We propose to sequence relevant portions of the Lrp5 gene in baboons to characterize genetic variation in this primate model for human bone maintenance and turnover. Exons 2,3,4,6,7,8, 9 and 10 of Lrp5 have been implicated in bone mass disorders and will be sequenced in 120 baboons for which we have existing data on BMD. The specific aims of this study are to: 1) sequence exons in Lrp5 known to affect BMD, 2) discover single nucleotide polymorphisms (SNPs) in these exons in SNPRC baboons, and 3) conduct analyses for tentative evidence of association between observed SNPs and BMD in the initial sample of baboons. This sequencing and SNP discovery will provide essential pilot data for a future application to the NIH to genotype another 556 animals for the SNPs identified in this study, thereby enabling a large scale association study to determine whether or not any of the discovered SNPs are associated with BMD variation.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 人类低密度脂蛋白受体相关蛋白5（Lrp 5）的突变是导致高骨密度和低骨密度（BMD）骨骼疾病的原因。近交系小鼠研究已经证实了Lrp 5突变对骨质量的几个方面的影响。Lrp 5基因的变异在多大程度上导致了普通人群中骨矿物质密度（BMD）的正常变异，这是目前深入研究的主题，因为大量的人受到骨脆性疾病如骨质疏松症的影响。最近的研究表明，Lrp 5多态性可能确实有助于群体水平的BMD变化。小鼠研究有助于确定Lrp 5对骨骼影响的潜在机制，但将这些远亲物种的研究结果外推到人类可能存在问题。狒狒的系统发育接近人类和随之而来的骨骼生理学和代谢的相似性，使其成为一个很好的模型，人类骨骼维护的遗传学研究。先前的一项研究显示，染色体11 q12 -13（Lrp 5区域）上的一个基因影响狒狒BMD的正常变化。我们建议对狒狒Lrp 5基因的相关部分进行测序，以表征这种灵长类动物模型中人类骨维持和周转的遗传变异。Lrp 5的外显子2、3、4、6、7、8、9和10与骨量紊乱有关，我们将对120只狒狒的BMD进行测序。本研究的具体目的是：1）对已知影响BMD的Lrp 5外显子进行测序，2）发现SNPRC狒狒这些外显子中的单核苷酸多态性（SNP），3）分析狒狒初始样本中观察到的SNP与BMD之间相关性的初步证据。这项测序和SNP发现将为NIH未来应用提供必要的试点数据，以针对本研究中确定的SNP对另外556只动物进行基因分型，从而能够进行大规模关联研究，以确定是否有任何发现的SNP与BMD相关变化。