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Genetic Environmental Relationship Between Bone Obesity and Leptin in Mice

小鼠骨肥胖与瘦素的遗传环境关系

基本信息

批准号：
8013377
负责人：
JAMES M CHEVERUD
金额：
$ 3万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-10 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013377
关键词：
Affect Age Animal Model Animals Autopsy Bioinformatics Biological Biological Assay Biomechanics Brain Candidate Disease Gene Characteristics Diabetes Mellitus Diet Dietary Factors Dietary Fats Disease Elderly Environment Environmental Risk Factor Evaluation Family history of Fasting Fat-Restricted Diet Fatty acid glycerol esters Fracture Gender Generations Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genome Genomics Genotype Goals Health Heritability Individual Inherited Kidney Knock-out Lead Leptin Light Liver Location Maps Measures Methods Modeling Morphologic artifacts Morphology Mouse Strains Mus Mutant Strains Mice Normal Range Obesity Osteoporosis Pathway interactions Phenotype Physiological Population Property Quantitative Trait Loci Recombinants Regulation Research Personnel Risk Risk Factors Role SM/J Mouse Series Signal Transduction Skeleton Specific qualifier value Testing Tissues Transgenic Mice Variant Weight Woman Work base bone bone mass bone strength cohort cost experience feeding gene environment interaction high standard interest men mouse model novel osteoporosis with pathological fracture overexpression programs research study response sex trait

项目摘要

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.

骨质疏松症和随之而来的骨折是老年人面临的一个重要健康问题。四大风险骨质疏松症的因素是年龄、性别、遗传倾向和肥胖。在这里，我们建议检查影响骨量、形态和生物力学特性的饮食和遗传因素，在已建立的肥胖、糖尿病和饮食性肥胖小鼠模型中，反应，LG/J和SM/J小鼠品系的交叉。通过这些研究我们将发现新的基因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性水平 LGXSM重组近交系（R1）中的性状及其与肥胖和瘦素水平的遗传相关性菌株来自每个品系的动物被喂食高脂肪或低脂肪饮食，使我们能够检查基因和环境（膳食脂肪）对骨特征和骨肥胖关系的影响。我们将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互交和F10高级互交（Al）品系群体。饲养所有动物，基因分型为以前的项目，并提供给这个项目在没有额外的费用。我们还将精细映射将这些QTL在A1系的F32代（N = 1000）中进行验证和精细定位早期的人口。与F2和F10代不同，完全肥胖、瘦素和糖尿病相关的将在F32动物中收集表型，并且动物将以高脂肪或低脂肪饮食饲养。在这一代的精细定位将使我们能够确定一个小的位置候选基因的集合，进一步评价。将检查这些基因的序列和表达多态性。强烈将在敲除和过表达转基因小鼠中评价支持的候选基因。这个项目将确定影响骨质疏松症的新基因和生理途径，并研究遗传和基于环境的肥胖影响骨量、形态和生物力学功能。