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风险因素。遗传基础的例子是同卵双胞胎中2型糖尿病的高度一致性，家族史对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，关键的环境因素已被确定，包括肥胖，不活动，次优的宫内环境，衰老，以及在细胞水平上，慢性高胰岛素血症，高血糖症和高脂血症，等等。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，我们假设非糖尿病个体中基因表达的改变具有发生糖尿病（“前驱糖尿病”）的高风险，介导了这种风险。 因此，我们建议利用高密度荧光素芯片来研究组织活检样本中的差异基因表达，这些样本来自具有代谢特征的糖尿病高危人群。这些研究应该使我们能够识别新的基因和表达序列标签（EST），这是负责糖尿病的发展。我们选择将重点放在“前驱糖尿病”，或临床疾病发生之前的时间段，以便在基因表达被高血糖症和其他明显疾病的代谢后果引起的继发性变化所掩盖之前，确定早期和潜在致病性的基因表达改变。因此，我们将把我们的努力集中在由特定风险因素定义的非糖尿病受试者组，这些风险因素包括：（1）遗传背景（阳性或阴性糖尿病家族史，根据当前代谢谱分层），（2）产前环境（低出生体重，根据当前代谢谱分层），（3）出生后环境，通过肥胖和/或胰岛素敏感性不一致的单卵双胞胎的差异表达进行评估。与此同时，我们将开始功能特性的基因证实，差异表达作为一个功能的糖尿病风险在多个风险亚组，通过使用小干扰RNA（siRNA），以干扰选定的基因在细胞培养模型的胰岛素作用。这些研究有助于确定糖尿病的病理生理学，并最终有助于开发更有效和更具体的预防和治疗2型糖尿病的方法。