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（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。遗传基础的例子包括同卵双胞胎中 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，还确定了关键的环境因素，包括肥胖、缺乏活动、子宫内环境欠佳、衰老以及细胞水平上的慢性高胰岛素血症、高血糖和高脂血症等。由于基因型和细胞环境都会在基因和蛋白质表达水平上影响细胞功能，因此我们假设非糖尿病个体中基因表达的改变具有患糖尿病（“前驱糖尿病”）的高风险，从而介导了这种风险。 因此，我们建议利用高密度寡核苷酸阵列来研究来自具有糖尿病发生高风险的代谢特征人类受试者的组织活检样本中的差异基因表达。这些研究应该使我们能够识别导致糖尿病发生的新基因和表达序列标签（EST）。我们选择关注“糖尿病前期”，即临床疾病发作之前的时间段，以便在基因表达的早期和潜在致病性改变被高血糖和其他代谢后果引起的继发性变化所掩盖之前定义它们的明显疾病。因此，我们将把工作重点放在由特定风险因素定义的非糖尿病受试者组上，包括（1）遗传背景（糖尿病家族史阳性或阴性，按当前代谢特征分层），（2）产前环境（低出生体重，按当前的代谢特征），（3）产后环境，通过肥胖和/或胰岛素敏感性不一致的同卵双胞胎中的差异表达进行评估。与此同时，我们将开始对已确认在多个风险亚组中作为糖尿病风险函数差异表达的基因进行功能表征，方法是使用小干扰RNA (siRNA) 使胰岛素作用细胞培养模型中选定的基因失活。这些研究应有助于定义糖尿病的病理生理学，并最终有助于开发更有效、更具体的预防和治疗 2 型糖尿病的方法。