EPIGENETIC MECHANISMS AND GENES ASSOCIATED WITH THE DEVELOPMENT OF ADIPOSITY

与肥胖发生相关的表观遗传机制和基因

• 批准号: 7720515
• 负责人: Robert A Koza
• 金额: $ 21.13万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720515
• 关键词: Adipose tissue; Adult; Age; Alleles; Animal Model; Animals; Biopsy; Computer Retrieval of Information on Scientific Projects Database; Development; Developmental Gene; Diabetes Mellitus; Diet; Dietary Fats; Disease; Elements; Environment; Epigenetic Process; Exposure to; Fatty acid glycerol esters; Funding; Future; Gene Expression; Genes; Genomics; Grant; Growth; Human; Individual; Institution; Link; Mesoderm; Mus; Nutritional status; Obesity; Phenotype; Regulation; Research; Research Personnel; Resources; Signal Transduction; Source; Transcript; Transgenic Organisms; United States National Institutes of Health; Variant; adipocyte differentiation; base; feeding; human SFRP4 protein; imprint; in utero; lipid biosynthesis; obesity treatment; programs; research study; therapeutic target

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. 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. Future experiments will evaluate these mechanisms and associated genes as potential therapeutic targets for the treatment of obesity.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 肥胖的发生是多因素的，包括变异等位基因和环境之间的相互作用，这些相互作用使个体容易患上该疾病。 基于表观遗传编程变化的肥胖的其他组成部分，已通过从人类流行病学和动物研究中获得的有力证据确定，这些研究将子宫内和产后早期生长期间的营养状况与成人肥胖和糖尿病的发展联系起来。 为了研究表观遗传对肥胖的影响，我们根据遗传相同的小鼠的肥胖表型变异开发了一种动物模型。 通过全局基因表达分析，我们在脂肪组织中确定了一组协调调节的发育基因，这些基因与小鼠在喂食高脂肪饮食后形成强大的肥胖表型有关。 这些基因包括 Wnt 信号传导拮抗剂、分泌型卷曲相关蛋白 5 (Sfrp5) 和印记基因中胚层特异性转录本 (Mest)。此外，在暴露于膳食脂肪之前对幼鼠进行的脂肪组织活检中Sfrp5和Mest表达的变化可以预测在较晚年龄最容易发生膳食脂肪诱导的肥胖的动物。 在本提案中，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。 我们还将鉴定与脂肪组织中 Sfrp5 和 Mest 可变表达相关的基因组靶标，以确定这些元件中是否存在表观遗传差异。 未来的实验将评估这些机制和相关基因作为治疗肥胖的潜在治疗靶点。