Integrated cellular, mouse and human research on a novel missense variant influencing adiposity in Samoans

关于影响萨摩亚人肥胖的新型错义变异的综合细胞、小鼠和人类研究

• 批准号: 9175412
• 负责人: Stephen T. McGarvey
• 金额: $ 78.5万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175412
• 关键词: Adipocytes; Adipose tissue; Behavioral; Biological; Biology; Body Weight; Body mass index; CREB3 gene; Cell Survival; Cell model; Cells; Cultured Cells; Data; Diet; Disease; Drosophila genus; Energy Metabolism; Environment; Environmental Risk Factor; Epidemiology; Ethnic group; Fatty acid glycerol esters; Funding; Future; Genes; Genetic; Genetic Epistasis; Genotype; Goals; Health; Heart Diseases; Heritability; High Prevalence; Homeostasis; Homologous Gene; Human; Individual; Intervention; Knock-in; Knock-in Mouse; Lead; Lipids; Mammals; Measures; Mediating; Medical Genetics; Metabolic; Metabolism; Minority; Mission; Molecular; Morbidity - disease rate; Multivariate Analysis; Mus; Nutritional; Obesity; Obesity associated disease; Organism; Outcome; Participant; Pathogenesis; Pathway interactions; Phenotype; Physical activity; Physiological; Population; Prevention; Preventive; Process; Public Health; Quantitative Trait Loci; Research; Resources; Role; Samoa; Samoan; Starvation; Stress; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcriptional Regulation; United States National Institutes of Health; Variant; Work; base; clinically relevant; fly; genetic approach; genetic variant; genome wide association study; human subject; improved; innovation; knock-down; lipid biosynthesis; mortality; multidisciplinary; novel; nutrition; obesity risk; obesity treatment; overexpression; oxidation; pleiotropism; prevent; response; risk variant; trait; transcription factor

PROJECT SUMMARY In this competitive renewal we focus on characterizing a novel missense variant that was identified by genome- wide association analysis (GWAS) of obesity-related traits in Samoans during the previous funding period. This missense variant is highly associated with body mass index (BMI) with an effect size greater than any other known common obesity risk variant. The gene harboring this missense variant encodes a putative transcription factor (TF) that has recently been implicated in energy metabolism in Drosophila but remains poorly characterized, particularly in higher organisms. Preliminary data presented in this application indicate that overexpression of both the wild-type human gene and its missense variant in 3T3L1 adipocytes enhances adipogenesis, promotes lipid storage, and improves cell survival. In addition, overexpression of the missense variant promotes even greater lipid storage and reduces energy substrate oxidation, suggesting that it is a “thrifty” variant. Given the enormous contribution of obesity to disease, additional studies are urgently needed to understand the mechanisms by which this missense variant contributes to obesity in humans. The Central Aim of this proposal is to determine how the TF gene and its missense variant contribute to energy homeostasis and to identify the transcriptional pathways mediating these effects. We will achieve this goal using integrated studies in cells, mice, and humans to understand the molecular, physiological, and clinical relevance of the missense variant. The following Specific Aims will be pursued: Aim 1 will identify and characterize the gene networks mediating the effects of the TF gene and its missense variant on energy homeostasis and energy substrate metabolism in cultured cells, a range of metabolically-relevant tissues from mice, and adipose tissue from 123 Samoans; Aim 2 will characterize the impact of the missense variant on whole body and tissue-specific energy homeostasis and energy substrate metabolism using variant-specific knockin mice; Aim 3 will more precisely characterize the impact of the missense variant on metabolic and behavioral traits that impact energy homeostasis in a subset of 500 Samoans GWAS participants who will be selected based on their genotype. These deeper phenotypes will be measured with new fieldwork in Samoa by re-contacting participants from the original GWAS study, during which metabolic and nutritional conditions/exposures analogous to those used in Aims 1 and 2 will be tested; Aim 4 will more fully characterize the missense variant using comprehensive statistical approaches including testing for selective signatures, testing for pleiotropy via multivariate analyses, performing pathway analyses, testing for missense variant x environment interactions with a focus on diet and physical activity, testing for TF gene x gene interactions focusing on genes identified in Aims 1 and 2, and testing for association with newly gathered phenotypes from Aim 3. Successful completion of these aims will promote the understanding of obesity and its downstream health outcomes as well as identify novel targets for pharmacological interventions.

项目摘要 在这种竞争性更新中，我们专注于表征一种新型的错觉变体，该变体是由基因组确定的 萨摩亚人肥胖相关性状的广泛关联分析（GWAS）在上一期资金期间。这 错义变体与体重指数（BMI）高度相关，其效果大小比任何其他 已知的普通肥胖风险变体。带有这种错义变体的基因编码推定的转录 因子（TF）最近与果蝇的能量代谢有关，但仍然很差 特征是，特别是在较高的生物体中。本应用程序中提供的初步数据表明 野生型人基因的过表达及其在3T3L1脂肪细胞中的错义变体增强 脂肪形成，促进脂质储存并改善细胞存活。此外，错过的过表达 变体促进更大的脂质储存并减少能量底物氧化，这表明它是一个 “节俭”的变体。鉴于肥胖对疾病的巨大贡献，迫切需要其他研究 了解这种错义变体有助于人类肥胖的机制。中央 该建议的目的是确定TF基因及其错义变体如何促进能量 稳态并确定介导这些影响的转录途径。我们将实现这个目标 使用细胞，小鼠和人类的综合研究来了解分子，物理和临床 错义变体的相关性。将追求以下具体目标：AIM 1将确定并 表征介导TF基因及其错义变体的基因网络对能量的影响 培养细胞中的稳态和能量底物代谢，这是一系列与代谢相关的组织 小鼠和来自123萨摩亚人的脂肪组织； AIM 2将表征错义变体对 全身和组织特异性能量稳态和能量底物代谢使用变体特异性 敲击小鼠； AIM 3将更精确地表征错义变体对代谢和 在500名萨摩亚人GWAS参与者中，会影响能量体内平衡的行为特征 根据其基因型选择。这些更深层次的表型将通过萨摩亚的新实地调查来测量 重新接触原始GWAS研究的参与者，在此期间代谢和营养 将测试类似于目标1和2中使用的条件/暴露； AIM 4将更充分地表征 使用全面统计方法的错义变体，包括选择性签名的测试， 通过多变量分析，进行途径分析，测试错义变体X测试多效性的测试 环境相互作用侧重于饮食和体育锻炼，测试TF基因X基因相互作用 专注于目标1和2中确定的基因，并测试与新收集的表型相关的基因 目标3。成功完成这些目标将促进对肥胖及其下游的理解 健康结果以及确定药物干预措施的新目标。