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

• 批准号: 7585768
• 负责人: JAMES M CHEVERUD
• 金额: $ 29.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-10 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585768
• 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

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.

骨质疏松症和随后的骨折是老年人面临的重要健康问题。四大风险 骨质疏松症的因素有年龄、性别、遗传倾向和肥胖。在这里我们建议检查 影响骨量、形态和生物力学特性的饮食和遗传因素以及 在已建立的肥胖、糖尿病和饮食小鼠模型中，这些特征与肥胖的关系 反应，LG/J 和 SM/J 小鼠品系的杂交。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力水平 LGXSM 重组近交系 (Rl) 的性状及其与肥胖和瘦素水平的遗传相关性 菌株。每个品系的动物都喂食高脂肪或低脂肪饮食，使我们能够检查其效果 基因和环境（膳食脂肪）对骨骼特征和骨骼与肥胖关系的影响。我们将 确定影响骨骼的基因组区域（数量性状位点，QTL）及其与肥胖的关系 R1品系、F2杂交和F10高级杂交(A1)品系群体。所有动物均被饲养并 对之前的项目进行了基因分型，并且可以免费用于本项目。我们也会细化地图 Al 系 F32 代 (N = 1000) 中的这些 QTL，以验证和精细定位发现的 QTL 与早期人群。与 F2 和 F10 代不同，完全肥胖、瘦素和糖尿病相关 将在 F32 动物中收集表型，并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出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 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 环境性肥胖影响骨量、形态和生物力学功能。