Epigenetic Mechanisms and Genes Associated with the Development of Adiposity

与肥胖发展相关的表观遗传机制和基因

基本信息

批准号：
7591263
负责人：
Robert A Koza
金额：
$ 22.05万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7591263
关键词：
3T3-L1 Cells Abbreviations Adipocytes Adipose tissue Adult Affect Age Alleles Animal Model Animals Biological Biological Assay Biopsy Cell Culture Techniques Cell Line Cells CpG Islands Deoxyribonuclease I Development Developmental Gene Diabetes Mellitus Diet Dietary Fats Disease Ear Elements Embryo Environment Epidemiology Epigenetic Process Exhibits Experimental Models Exposure to Fatty acid glycerol esters Fibroblasts Future Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Variation Genome Genomics Growth Heterogeneity Histone Acetylation Histones Human Hypersensitivity Immunoglobulin Variable Region In Vitro Inbred Strains Mice Individual Laboratories Link Lipids MEST protein Maps Mesenchymal Stem Cells Mesoderm Methylation Modeling Modification Mus Nutritional status Obesity Pathway interactions Phenotype Predisposition RNA Regulation Regulatory Element Reporter Retroperitoneal Space Role Signal Transduction Site System Testing Tissues Transcript Transgenic Organisms Variant Vascularization Weight Gain adipocyte differentiation angiogenesis base bisulfite cell growth epigenetic variation feeding glucose uptake human SFRP4 protein imprint in utero lipid biosynthesis lipid metabolism male mouse model obesity treatment programs public health relevance research study therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): The development of obesity is multifactorial and includes interactions between variant alleles and environments that predispose individuals toward development of the disease. Other components of obesity, based on variations in epigenetic programming, have been established by the strong evidence obtained from human epidemiological and animal studies that link nutritional status during in utero and early post-natal growth to the development of obesity and diabetes in adults. However, the mechanisms associated with these epigenetic contributions to obesity are difficult to study because of the lack of a good experimental model or appropriate gene targets. To investigate epigenetic contributions to obesity, we have developed an animal model based upon phenotypic variation of obesity in genetically identical mice. Using global gene expression analyses, we have identified a set of coordinately regulated developmental genes in adipose tissue that are associated with the development of a robust obesity phenotype in mice after feeding a high fat diet. These genes include an antagonist of Wnt signaling, secreted frizzled related protein 5 (Sfrp5) and the imprinted gene mesoderm specific transcript (Mest). Additionally, variations of Sfrp5 and Mest expression in adipose tissue biopsies performed on young mice prior to exposure to dietary fat can predict animals that were most susceptible to the development of dietary fat- induced obesity at a later age. In this proposal, we will use a retroviral-delivered inducible transgenic approach to examine the mechanism associated with the coordinated regulation of Sfrp5 and Mest and to determine how these genes modulate lipogenesis and adipocyte differentiation. We will also identify genomic targets associated with variable expression of Sfrp5 and Mest in adipose tissue to determine whether epigenetic differences are present within these elements. The results of these experiments will begin to elucidate unique biological mechanisms linked to epigenetic programming that are associated with variations of adiposity in the absence of genetic variation. Future experiments will evaluate these mechanisms and associated genes as potential therapeutic targets for the treatment of obesity. PUBLIC HEALTH RELEVANCE Many studies have shown that nutritional status during development can permanently alter an individual's susceptibility to developing diseases such as obesity and diabetes, however, very little is known about the biological mechanisms that cause these changes. Therefore, we characterized a mouse model that has no genetic differences between individuals to study the basis for these permanent alterations, and have identified several genes that are associated with variations in obesity. We propose to study how two of these genes, mesoderm specific transcript and secreted frizzled related protein 5, function in order to determine whether they could be good therapeutic targets for the treatment of obesity.

描述（由申请人提供）：肥胖的发展是多因素的，包括变体等位基因和环境之间的相互作用，使个人倾向于疾病的发展。肥胖的其他组成部分基于表观遗传程序的变化，是通过从人类流行病学和动物研究中获得的强有力的证据来确定的，这些证据与子宫内的营养状况联系起来，在产后早期生长与成人肥胖和糖尿病的发展相关。但是，由于缺乏良好的实验模型或适当的基因靶标，与这些表观遗传学贡献相关的机制很难研究。为了研究对肥胖症的表观遗传学贡献，我们基于遗传相同小鼠肥胖的表型变化开发了动物模型。使用全球基因表达分析，我们已经确定了脂肪组织中的一组协调调控的发育基因，这些基因与高脂肪饮食后小鼠的稳健肥胖表型有关。这些基因包括Wnt信号传导的拮抗剂，分泌的毛躁相关蛋白5（SFRP5）和印迹基因中胚层特异性转录本（MEST）。此外，在暴露于饮食脂肪之前，SFRP5和对年轻小鼠进行的脂肪组织活检中的表达变化可以预测那些最容易受到饮食脂肪诱发的肥胖症的影响。在此提案中，我们将使用逆转录病毒诱导的转基因方法来检查与SFRP5和MEST协调调节相关的机制，并确定这些基因如何调节脂肪生成和脂肪细胞分化。我们还将确定与SFRP5和脂肪组织中MEST可变表达相关的基因组靶标，以确定在这些元素中是否存在表观遗传差异。这些实验的结果将开始阐明与表观遗传学编程相关的独特生物学机制，这些机制与没有遗传变异的情况下与肥胖的变化有关。未来的实验将评估这些机制和相关基因作为治疗肥胖症的潜在治疗靶点。公共卫生相关性许多研究表明，发育过程中的营养状况可以永久改变个人对肥胖和糖尿病等疾病的敏感性，但是，对导致这些变化的生物学机制知之甚少。因此，我们表征了一个小鼠模型，该模型在个体之间没有遗传差异来研究这些永久性改变的基础，并确定了与肥胖症变化相关的几种基因。我们建议研究这些基因中的两个，中胚层特定的转录本和分泌的毛躁相关蛋白5，以确定它们是否可以成为治疗肥胖症的良好治疗靶标。