Genetic Environmental Relationship Between Bone Obesity and Leptin in Mice

骨质疏松症和继发性骨折是老年人面临的一个重要健康问题。四大风险 导致骨质疏松症的因素有年龄、性别、遗传倾向和肥胖。在这里，我们建议研究一下 影响骨量、形态和生物力学特性的饮食和遗传因素以及 在建立的肥胖、糖尿病和饮食的小鼠模型中，这些特征与肥胖的关系 反应，LG/J和SM/J小鼠品系杂交。通过这些研究，我们将发现新的基因 以及影响骨骼的途径及其与肥胖的关系。我们将测量骨骼的遗传力水平 LGXSM重组自交系的性状及其与肥胖和瘦素水平的遗传相关性 菌株。每个品系的动物都被喂以高脂肪或低脂肪的饮食，这让我们能够检查 基因和环境(饮食脂肪)对骨骼特征和骨肥胖关系的影响。我们会 确定影响骨骼的基因组区域(数量性状基因座，QTL)及其与肥胖的关系 RL品系、F2杂交和F10高级杂交(Al)系群体。所有的动物都被饲养和饲养 为以前的项目进行基因分型，并提供给这个项目，不需要额外的费用。我们还将绘制精细地图 这些QTL在Al系(N=1000)的F32世代中用于验证和精细定位所发现的QTL 与更早的种群。与F2和F10代不同，完全肥胖、瘦素和糖尿病相关 表型将被收集在F32动物中，动物将被饲养在高脂肪或低脂肪饮食中。 这一代的精细作图将使我们能够识别一小组位置候选基因 进一步评估。将检查这些基因的序列和表达多态性。强烈地 支持的候选基因将在敲除和过度表达的转基因小鼠中进行评估。这个项目 将识别影响骨质疏松症的新基因和生理途径，并研究遗传和 环境性肥胖会影响骨量、形态和生物力学功能。

Osteoporosis and subsequent fractures are an important health problem facing the elderly. Four major risk factors for osteoporosis are age, gender, genetic predisposition, and obesity. Here we propose to examine dietary and genetic factors affecting bone mass, morphology, and biomechanical properties and the relationships of these features to obesity in an established mouse model for obesity, diabetes, and dietary response, the cross of LG/J and SM/J mouse strains. Through these studies we will discover novel genes and pathways affecting bone and its relationship to obesity. We will measure the level of heritability for bone traits and their genetic correlations with obesity and leptin levels in the LGXSM Recombinant Inbred (Rl) strains. Animals from each strain have been fed a high or low fat diet allowing us to examine the effects of both genes and environment (dietary fat) on bone characteristics and bone-obesity relationships. We will identify genomic regions (Quantitative Trait Loci, QTLs) affecting bone and its relationship to obesity in the Rl strains, F2 intercross, and an F10 Advanced Intercross (Al) line population. All animals were reared and genotyped for previous projects and are available to this project at no additional cost. We will also fine-map these QTLs in the F32 generation of the Al Line (N = 1000) to validate and fine-map the QTLs discovered with earlier populations. Unlike the F2 and F10 generations, complete obesity, leptin, and diabetes-related phenotypes will be collected in the F32 animals and animals will be reared on either a high or low fat diet. Fine-mapping in this generation will allow us to identify a small set of positional candidate genes for for further evaluation. Sequence and expression polymorphism will be examined for these genes. Strongly supported candidate genes will be evaluated in knock-out and overexpressing transgenic mice. This project will identify novel genes and physiological pathways affecting osteoporosis and examine how genetic and environmentally-based obesity affects bone mass, morphology and biomechanical function.