PROTEOMIC ANALYSIS OF MURINE MODELS OF OSTEOPOROSIS

骨质疏松症小鼠模型的蛋白质组学分析

• 批准号: 8365488
• 负责人: ROBERT FREDERICK KLEIN
• 金额: $ 2.87万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8365488
• 关键词: Applications Grants; Biochemical Pathway; Biological Markers; Biology; Blood capillaries; Clinical; Complex; Congenic Mice; Congenic Strain; Data; Databases; Disease; Early Diagnosis; Fasting; Female; Fourier transform ion cyclotron resonance; Fracture; Functional disorder; Funding; Genes; Genetic; Genetic Variation; Genome; Grant; Heterogeneity; Human; Inbreeding; Knowledge; Laboratory mice; Maintenance; Maps; Methods; Modeling; Molecular Profiling; Mouse Strains; Mus; National Center for Research Resources; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Osteoporosis; Plasma; Predisposition; Principal Investigator; Protein Analysis; Proteome; Proteomics; Relative (related person); Reporting; Research; Research Infrastructure; Resources; Risk; Sampling; Signal Transduction; Source; Techniques; Trauma; United States National Institutes of Health; bone mass; bone strength; capillary; congenic; congenic breeding; cost; functional genomics; genetic analysis; improved; insight; mouse model; patient population; skeletal

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Introduction: Osteoporosis is a multifactorial disease characterized by reduced bone strength and increased susceptibility to low trauma fracture. Although a strong genetic contribution to osteoporosis and fracture is well documented, the genes and allelic variants conferring risk remain largely undefined. There is now an ongoing effort using modern genetic analyses to map the chromosomal loci of genes responsible for heritable differences in osteoporosis risk. While recent clinical reports show promise, unraveling the genetic influences on a complex disease like osteoporosis is a formidable challenge in humans because of the genetic and cultural heterogeneity of patient populations. Through the support of NIAMS, we have employed a congenic breeding strategy to develop different strains of laboratory mice with improved bone strength. Hypothesis: When applied to congenic mouse models with uniform genetic and environmental backgrounds, the high sensitivity, high dynamic range capillary LC-FTICR proteomic techniques developed at the PNNL NCRR Resource Center will identify biologically relevant molecular signatures and provide new insights into the pathophysiology of osteoporosis. Methods and Results: 1. Develop a database for the normal mouse plasma proteome, using fasting samples obtained from 10 female C57BL/6 inbred control mice. 2. Develop a database for the plasma proteome of two mice with improved bone strength, using fasting plasma samples from 10 female mice from two different congenic strains (both of which share the C57BL/6 background genome). 3. Perform quantitative analysis of protein abundances in the blood plasma in the two improved bone strength strains relative to the control mouse strain and each other. Discussion: Comparison of the proteome data from the background (C57BL/6) low bone mass mice and the two congenic high bone mass strains along with the knowledge of the different introgressed chromosomal regions in each of the congenic strains will allow for identification of biochemical pathways, networks and signaling nodes involved in the attainment and maintenance of skeletal integrity. These initial findings will be used as preliminary data for a subsequent grant application that will employ targetted proteomic, genomic and functional analyses of our murine models to further characterize the pathogenetic underpinnings of skeletal fragility and perhaps even identify biomarkers for early diagnosis of increased osteoporosis risk.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 介绍：骨质疏松症是一种多因素疾病，其特征是骨强度降低和对低创伤骨折的易感性增加。虽然骨质疏松症和骨折的基因贡献很大，但赋予风险的基因和等位基因变异在很大程度上仍不确定。目前正在努力利用现代遗传分析来绘制与骨质疏松症风险的遗传差异有关的基因的染色体位点。虽然最近的临床报告显示出希望，但由于患者群体的遗传和文化异质性，解开遗传对骨质疏松症等复杂疾病的影响是人类面临的巨大挑战。通过NIAMS的支持，我们采用了同源育种策略，开发了不同品系的实验室小鼠，提高了骨强度。 假设：当应用于具有统一遗传和环境背景的同类小鼠模型时，在PNNL NCRR资源中心开发的高灵敏度，高动态范围毛细管LC-FTICR蛋白质组学技术将识别生物学相关的分子特征，并为骨质疏松症的病理生理学提供新的见解。 方法和结果： 1.使用从10只雌性C57 BL/6近交系对照小鼠获得的禁食样品，建立正常小鼠血浆蛋白质组数据库。 2.使用来自两种不同同源品系（两者都具有C57 BL/6背景基因组）的10只雌性小鼠的空腹血浆样本，开发两种骨强度改善小鼠的血浆蛋白质组数据库。3.相对于对照小鼠品系和两种改良骨强度品系，对血浆中蛋白质丰度进行定量分析。 讨论内容：比较来自背景（C57 BL/6）低骨量小鼠和两个同源高骨量品系沿着的蛋白质组数据以及对每个同源品系中的不同渐渗染色体区域的了解，将允许鉴定参与骨骼完整性的获得和维持的生化途径、网络和信号传导节点。这些初步发现将被用作后续拨款申请的初步数据，该申请将采用我们小鼠模型的靶向蛋白质组学，基因组学和功能分析，以进一步表征骨骼脆弱性的发病基础，甚至可能确定用于早期诊断骨质疏松症风险增加的生物标志物。