Genetic Environmental Relationship Between Bone, Obesity and Leptin in Mice

描述(申请人提供)：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。骨质疏松症的四个主要风险因素是年龄、性别、遗传倾向和肥胖。在这里，我们建议在建立的肥胖、糖尿病和饮食反应的小鼠模型(LG/J和SM/J小鼠品系的杂交)中，检查饮食和遗传因素对骨量、形态和生物力学特性的影响，以及这些特征与肥胖的关系。通过这些研究，我们将发现影响骨骼及其与肥胖的关系的新基因和新途径。我们将在LGXSM重组近交系(RL)中测量骨骼特征的遗传力水平及其与肥胖和瘦素水平的遗传相关性。每个品系的动物都被喂以高脂或低脂饮食，这让我们能够检查基因和环境(饮食脂肪)对骨骼特征和骨骼肥胖关系的影响。我们将在RL品系、F2杂交和F10高级杂交(Al)系群体中识别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。所有动物都是在以前的项目中饲养并进行基因分型的，可以免费提供给这个项目。我们还将在Al系(N=1000)的F32代中对这些QTL进行精细定位，以验证和精细定位在早期群体中发现的QTL。与F2和F10代不同，F32代动物将收集完全肥胖、瘦素和糖尿病相关的表型，并将以高脂肪或低脂肪饮食饲养动物。这一代的精细作图将使我们能够识别一小部分位置候选基因，以便进一步评估。将检查这些基因的序列和表达多态性。强烈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。该项目将确定影响骨质疏松症的新基因和生理途径，并研究遗传性和环境性肥胖如何影响骨量、形态和生物力学功能。

DESCRIPTION (provided by applicant): 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 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.