MOLECULAR DISSECTION OF REGIONAL ADIPOSITY

局部肥胖的分子解剖

• 批准号: 6675941
• 负责人: CYNTHIA M SMAS
• 金额: $ 14.7万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6675941
• 关键词: adipocytes; adipose tissue; body regions; body weight; brown fat; comorbidity; cytogenetics; differential display technique; functional /structural genomics; gene expression; genetic regulation; genetically modified animals; high throughput technology; laboratory mouse; metabolism disorder; microarray technology; molecular cloning; molecular genetics; obesity; peritoneal cavity; phenotype; polymerase chain reaction; skin; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Obesity is a growing national health concern and it is closely linked to comorbidities of cardiovascular disease and diabetes. Population-based studies have indicated a strong association between regional location of excess adipose tissue and health impact, with intra-abdominal visceral adiposity resulting in the most deleterious effects. Studies in humans and rodents indicate that each white adipose tissue (WAT) depot has unique physiological and metabolic profiles. However, the gene expression patterns underlying these phenotypic distinctions have received very limited study and no gene with expression exclusive to adipocytes from one or another particular WAT depot has been described. To address the hypothesis that each WAT depot is transcriptionally distinct, we have prepared and differentially screened a murine WAT depot subtracted library and conducted pilot filter DNA array hybridization studies. Using the mouse as a model system, studies in this R21 proposal further delineate the gene expression differences between adipocytes found in each of four distinct WAT depots - omental, subcutaneous, epididymal and retroperitoneal from wild type and obese sources. These transcriptional profiles will yield critical insights into how differences in gene expression of adipocytes in various WAT depots lead to pathophysiology of regional adiposity. Two specific aims will be conducted: 1.) Utilizing DNA microarray, subtracted cloning, and differential display, we will characterize profiles of white adipocyte depot-specific gene expression. 2.) In vitro cell culture models for the high throughput study of WAT depot specific gene expression will be generated and validated. The long-term goal of this research is to identify DNA elements and their cognate transcription factors that function in WAT depot specification and gene expression in vivo. This knowledge will be used to define the molecular mechanisms that result in pathophysiology and co-morbidities of regional obesity and to design WAT depot-specific promoter constructs to conduct targeted ablation studies. Only in this way can the contribution of a particular WAT depot to health and disease be assessed and modulated in vivo; such experiments are not feasible with current molecular tools. The completion of the research plan in this R21 proposal will be a critical step in achieving these long-term goals.

描述（由申请人提供）：肥胖是一个日益增长的国家健康问题，它与心血管疾病和糖尿病的合并症密切相关。基于人群的研究表明，脂肪组织过多的区域位置与健康影响之间存在密切的关联，腹内内脏肥胖量导致最有害的作用。对人类和啮齿动物的研究表明，每个白色脂肪组织（WAT）仓库具有独特的生理和代谢谱。然而，这些表型区分的基因表达模式已经得到了非常有限的研究，并且没有描述来自一个或另一个特定WAT仓库的脂肪细胞独有的基因。为了解决每个WAT仓库在转录上不同的假设，我们已经准备好并鉴定筛选了鼠WAT仓库减去库，并进行了试验过滤器DNA阵列杂交研究。使用小鼠作为模型系统，在此R21提案中研究进一步描述了在四个不同的WAT库中发现的脂肪细胞之间的基因表达差异 - 来自野生型和肥胖来源的四个不同的WAT库 - 胶质，皮下，附子和腹膜。这些转录曲线将对各种WAT库中脂肪细胞基因表达的差异如何导致区域肥胖的病理生理学产生关键见解。将进行两个具体的目的：1。）利用DNA微阵列，减去克隆和差异显示，我们将表征白色脂肪细胞特异性基因表达的曲线。 2.）将生成和验证WAT库特异性基因表达的高吞吐量研究的体外细胞培养模型。这项研究的长期目标是鉴定DNA元素及其在体内作用和基因表达中起作用的同源转录因子。这些知识将用于定义导致区域肥胖症的病理生理和合并症的分子机制，并设计WAT仓库特异性启动子构建体以进行有针对性的消融研究。只有这样，在体内评估和调节特定的WAT量表对健康和疾病的贡献才能；当前的分子工具对于此类实验是不可行的。该R21提案中的研究计划的完成将是实现这些长期目标的关键一步。