The effects of allelic variation in Pparg on skeletal metabolism

Pparg 等位基因变异对骨骼代谢的影响

• 批准号: 7332615
• 负责人: Cheryl Lynne Ackert-Bicknell
• 金额: $ 1.73万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-07 至 2008-01-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7332615
• 关键词: 2,4-thiazolidinedione; Adipocytes; Adverse effects; Affect; Age; Age-Related Bone Loss; Alleles; American; Animals; Architecture; Biological; Biological Assay; Biology; Bone Density; Bone Marrow; Chromosomes, Human, Pair 6; Congenic Mice; Diabetes Mellitus; Diet; Dietary Fats; Disease Progression; Distal; Equilibrium; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Femur; Gene Expression; Genes; Genetic; Genetic Polymorphism; Goals; Hepatic; Histology; Homeostasis; Human; In Vitro; Inbred Strain; Inbred Strains Mice; Insulin-Like Growth Factor I; Ligands; Liver; Maintenance; Maps; Marrow; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Numbers; Obesity; Osteoblasts; Osteoporosis; PPAR gamma; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Play; Polymerase Chain Reaction; Polyunsaturated Fatty Acids; Proteins; Public Health; Quantitative Trait Loci; Reporting; Research; Risk; Role; Serum; Single Nucleotide Polymorphism; Skeletal system; Surrogate Markers; Thiazolidinediones; Time; Variant; Western Blotting; Women' s Group; adipocyte differentiation; base; bone; bone growth factor; bone loss; congenic; day; density; diabetic; feeding; genetic association; in vivo; insight; prevent; promoter; response; rosiglitazone; substantia spongiosa

DESCRIPTION (provided by applicant): Project summary: Currently 55% of American over the age of 50 have or are at risk for osteoporosis. The long term objective of this proposal is to characterize the impact of allelic variation in the Peroxisome Proliferator Activated Receptor Gamma (Pparg) gene on skeletal metabolism during activation of this nuclear receptor by dietary or synthetic ligand. The B6.C3H-6T (6T) mouse, a model of human age related bone loss, carries alleles from the C3H/HeJ strain for Pparg, on an otherwise C57BL/6J (B6) background, and has low Bone Mineral Density (BMD). Dietary fat is an activator of PPARG protein and has been found to interact with allelic variation in Pparg to influence BMD. More specifically, feeding a high fat diet results in low BMD in 6T but not B6 mice. A similar interaction has been found in humans. The first specific aim of this proposal is to identify and characterize the molecular pathways by which dietary fat impacts bone acquisition. Gene expression of key genes that affect or are targets of PPARG will be examined by high throughput Quantitative Real Time PCR (QPCR), in liver and femur from B6 and 6T mice fed a high or a low fat diet. Approximately 21 % of Americans over the age of 60 currently have diabetes. Thiazolidinediones (TZDs) are popular drugs for the treatment of Type II diabetes, are ligands for PPARG, and have been shown to negatively affect BMD. In the second specific aim, the in vivo consequences of PPARG activation by, Rosiglitazone (a TZD), will be characterized to determined the impact on skeletal maintenance. Groups of female B6 and 6T mice will be treated with Rosiglitazone (20 mg/kg/day) for 8 wks. Femurs will be collected and phenotyped for BMD, bone architecture and marrow adiposity. In a separate, but identically treated group of mice, bones and livers will be collected and the expression of key genes identified in Aim One will be examined by QPCR. The goal of this aim is to to ascertain differences and similarities between activation of PPARG by either dietary fat or Rosi. Insulin-like Growth factor-1 is a key growth factor for bone and in vitro is negatively regulated by PPARG. Treatment with Rosiglitazone will be expanded to include 5 inbred strains to determine if serum IGF-1 is a convenient surrogate marker for bone loss induced by Rosiglitazone. Relevance to Public Health: This research will determine why a high fat diet results in low bone density, in people carrying certain versions of the PPARG gene. In addition, Rosiglitazone is a common Type 2 Diabetes drug which acts on PPARG, but treatment with this drug may also decrease bone density. This research will determine if Rosiglitazone affects bone and under what circumstances.

描述（由申请人提供）：项目摘要：目前55%的美国50岁以上的人患有骨质疏松症或有患骨质疏松症的风险。本提案的长期目标是表征过氧化物酶体激活受体γ（Pparg）基因中等位基因变异在通过饮食或合成配体激活该核受体期间对骨骼代谢的影响。B6.C3H-6 T（6 T）小鼠是人类年龄相关性骨丢失的模型，其携带来自C3 H/HeJ品系的Pparg等位基因，在另外的C57 BL/6 J（B6）背景上，并且具有低骨矿物质密度（BMD）。膳食脂肪是PPARG蛋白的激活剂，并且已发现与PPARG中的等位基因变异相互作用以影响BMD。更具体地说，喂食高脂肪饮食导致6 T小鼠而不是B6小鼠的低BMD。在人类中也发现了类似的相互作用。该提案的第一个具体目标是确定和表征膳食脂肪影响骨获得的分子途径。通过高通量定量真实的时间PCR（QPCR）在来自饲喂高或低脂饮食的B6和6 T小鼠的肝脏和股骨中检查影响PPARG或作为PPARG靶标的关键基因的基因表达。大约21%的60岁以上的美国人目前患有糖尿病。噻唑烷二酮（TZD）是治疗II型糖尿病的常用药物，是PPARG的配体，并已显示对BMD有负面影响。在第二个具体目标中，将表征罗格列酮（TZD）激活PPARG的体内结果，以确定对骨骼维持的影响。雌性B6和6 T小鼠组将用罗格列酮（20 mg/kg/天）处理8周。将收集股骨并对BMD、骨结构和骨髓肥胖进行表型分析。在单独但相同处理的小鼠组中，将收集骨骼和肝脏，并通过QPCR检查Aim One中鉴定的关键基因的表达。该目的的目的是确定膳食脂肪或Rosi激活PPARG之间的差异和相似性。胰岛素样生长因子-1是骨的关键生长因子，在体外受PPARG负调控。罗格列酮治疗将扩大到包括5个近交系，以确定血清IGF-1是否是罗格列酮诱导的骨丢失的方便替代标志物。与公共卫生的相关性：这项研究将确定为什么高脂肪饮食会导致携带某些PPARG基因的人骨密度低。此外，罗格列酮是一种常见的2型糖尿病药物，作用于PPARG，但用这种药物治疗也可能降低骨密度。这项研究将确定罗格列酮是否影响骨骼以及在什么情况下影响骨骼。