Gene Expression in Prediabetes: Potential Role of PGC-1

糖尿病前期的基因表达：PGC-1 的潜在作用

• 批准号: 6838129
• 负责人: Mary E Patti
• 金额: $ 5.83万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838129
• 关键词: Gene; Expression; Prediabetes; Potential; Role

DESCRIPTION (provided by applicant): Both genetics and environment are critical risk factors in the epidemic of type 2 diabetes. The genetic basis is exemplified by the high degree of concordance of type 2 diabetes in identical twins, the strong influence of family history on the risk of developing diabetes, and the high incidence of diabetes in certain ethnic populations. In addition, criticalenvironmental factors have been identified, including obesity, inactivity, a suboptimal intrauterine environment, aging, and, at a cellular level, chronic hyperinsulinemia, hyperglycemia, and hyperlipidemia, among others. Since both genotype and cellular environment converge to influence cellular function at the level of gene and protein expression, we hypothesize that alterations in gene expression in nondiabetic individual sat high risk for developing diabetes ("prediabetes') mediate this risk. Thus, we propose to utilize high density oligonucleotidearrays to study differential gene expression in tissue biopsy samples from metabolically characterized human subjects at high risk for the development of diabetes. These studies should permit us to identify novel genes and expressed sequence tags (ESTs), which are responsible for the development of diabetes. We have chosen to focus on "prediabetes," or the time period prior to the onset of clinical disease, in order to define early, and potentially pathogenic, alterations in gene expression before they are obscured by secondary changes resulting from hyperglycemia and other metabolic consequences of overt disease. Thus, we will direct our efforts on nondiabetic subject groups defined by specific riskfactors, including (1) genetic background (positive or negative family history of diabetes, stratified by current metabolic profile), (2) prenatal environment (low birth weight, stratified by current metabolic profile), (3) postnatal environment, assessed by differential expression in monozygotic twins discordant for obesity and/or insulin sensitivity. In parallel, we will begin functional characterization of genes confirmed to be differentially expressed as a function of diabetes risk in multiple risk subgroups, by using small interfering RNA (siRNA) to inactivate selected genes in cell culture models of insulin action. These studies should help to define pathophysiology of diabetes and ultimately help to develop more effective and specific methods of prevention and treatment of type 2 diabetes.

描述（由申请人提供）：遗传和环境都是2型糖尿病流行的关键危险因素。遗传基础体现在同卵双胞胎患2型糖尿病的高度一致性，家族史对患糖尿病风险的强烈影响，以及某些种族人群中糖尿病的高发病率。此外，已经确定了关键的环境因素，包括肥胖、缺乏活动、次优的宫内环境、衰老，以及细胞水平上的慢性高胰岛素血症、高血糖症和高脂血症等。由于基因型和细胞环境在基因和蛋白质表达水平上共同影响细胞功能，我们假设非糖尿病高危人群（“前驱糖尿病”）的基因表达改变介导了这种风险。