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风险因素。遗传基础的例证是同卵双胞胎中2型糖尿病的高度一致性，家族病史对患糖尿病风险的强烈影响，以及某些民族人群中糖尿病的高发病率。此外，已确定的关键环境因素包括肥胖、不活动、不理想的宫内环境、衰老，以及在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的基因表达改变对糖尿病(“前驱糖尿病”)具有很高的风险。 因此，我们建议利用高密度寡核苷酸阵列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)，它们与糖尿病的发展有关。我们选择关注“糖尿病前期”，即临床疾病发作前的一段时间，以便在高血糖和其他显性疾病的代谢后果导致的继发性变化掩盖之前，定义早期的、潜在的致病性基因表达变化。因此，我们将努力针对由特定风险因素定义的非糖尿病受试者群体，包括(1)遗传背景(糖尿病阳性或阴性家族史，按当前代谢状况分层)，(2)产前环境(低出生体重，按当前代谢状况分层)，(3)出生后环境，通过不利于肥胖和/或胰岛素敏感性的同卵双胞胎的差异表达来评估。同时，我们将通过使用小干扰RNA(SiRNA)在胰岛素作用的细胞培养模型中失活选定的基因，开始对在多个风险亚组中被证实为糖尿病风险函数的差异表达的基因进行功能鉴定。这些研究应该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。