ENDOPLASMIC RETICULUM STRESS RESPONSE IN HUMAN TYPE 2 DIABETES

人类 2 型糖尿病的内质网应激反应

• 批准号: 7377697
• 负责人: Steven C Elbein
• 金额: $ 0.42万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377697
• 关键词: ENDOPLASMIC; RETICULUM; STRESS; RESPONSE; HUMAN

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 2 diabetes (T2DM) is a common, inherited disease that appears to result from a large number of common DNA sequence variants. Despite extensive investigation, the early pathological events in humans remain uncertain. Recent animal data suggest that a pathway common to all cells and all organisms, the endoplasmic reticulum stress response (ERSR) is activated in adipocytes and hepatocytes with obesity, and likely in pancreatic $-cells, but no human data are available. We will combine human physiological and molecular studies with a genomics approach to identify sequence variants in the extensive transcription cascade that is initiated with the response to unfolded proteins and may lead to protein degradation, altered transcription, and cellular apoptosis. We hypothesize that 1) ERSR is activated in subcutaneous adipose tissue from both glucose tolerant obese individuals and individuals with impaired glucose tolerance relative to nonobese, healthy, glucose tolerant individuals, that these pathways are downregulated by thiazolidinediones in adipocytes, and that common cis-acting DNA sequence variants alter the expression of key ERSR genes and increase susceptibility to T2DM. To test these hypotheses we propose four Specific Objectives, of which only the first is proposed at present for IRB and GCRC approval. We will test 40 individuals in each of 3 groups (normoglycemic, lean controls; obese, normoglycemic individuals, and individuals with impaired glucose tolerance) in two ethnic groups, African American and Caucasian. We will characterize insulin sensitivity using the intravenous glucose tolerance test and Minimal Model, and will obtain adipose and muscle by needle biopsy. W e will determine ERSR by measuring transcription and phosphorylation of key ERSR genes. In subsequent aims, to be performed using tissues gathered in this an other ongoing studies, we will measure the change in transcription of the most significant genes in adipose and muscle before and after treatment with pioglitazone, and we will use a novel approach to identify cis-acting sequence variants in ERSR genes by testing adipose, muscle, and epstein-bar virus transformed lymphocytes for evidence of an imbalance in mRNA levels. Finally, we will examine each gene which shows evidence for altered transcription or RNA stability by searching for additional coding or regulatory sequence variants, establishing the associations between these variants in a population (haplotype structure), and testing those variants that identify these haplotypes for an association with T2DM, insulin resistance, and disordered insulin secretion. Only studies of Aim 1 are proposed at the present time, and will seek to collect pilot data that may be used to prepare an application to NIH to provide adequate funding to perform the proposed studies. This work will eventually identify potential genetic variants that might provide drug targets or a means to identify individuals who would benefit from drugs aimed at altering ERSR gene transcription. This work thus has the potential to have a direct impact on the prevention and care of T2DM and metabolic syndrome.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。 2型糖尿病（T2DM）是一种常见的遗传疾病，似乎是由大量常见的DNA序列变体引起的。尽管进行了广泛的调查，但人类的早期病理事件仍然不确定。最近的动物数据表明，所有细胞和所有生物的途径，内质网应激反应（ERSR）在具有肥胖症的脂肪细胞和肝细胞中被激活，并且可能在胰腺$细胞中激活，但没有人类数据可用。我们将将人类的生理和分子研究与基因组学方法相结合，以鉴定广泛转录级联反应的序列变异，这些变体是随着对展开蛋白的反应而引发的，并可能导致蛋白质降解，转录改变和细胞凋亡。 We hypothesize that 1) ERSR is activated in subcutaneous adipose tissue from both glucose tolerant obese individuals and individuals with impaired glucose tolerance relative to nonobese, healthy, glucose tolerant individuals, that these pathways are downregulated by thiazolidinediones in adipocytes, and that common cis-acting DNA sequence variants alter the expression of key ERSR genes and increase对T2DM的敏感性。为了检验这些假设，我们提出了四个特定的目标，目前仅提出了第一个目标以供IRB和GCRC批准。我们将在两个族裔群体（非裔美国人和高加索人）中测试3个组中的40个（正常血糖，瘦肉控制；肥胖，正常血糖个体和葡萄糖耐受性受损的个体）。我们将使用静脉葡萄糖耐受性测试和最小模型来表征胰岛素敏感性，并通过针头活检获得脂肪和肌肉。我们将通过测量关键ERSR基因的转录和磷酸化来确定ERSR。 In subsequent aims, to be performed using tissues gathered in this an other ongoing studies, we will measure the change in transcription of the most significant genes in adipose and muscle before and after treatment with pioglitazone, and we will use a novel approach to identify cis-acting sequence variants in ERSR genes by testing adipose, muscle, and epstein-bar virus transformed lymphocytes for evidence of an imbalance in mRNA水平。最后，我们将检查每个基因，这些基因通过寻找其他编码或调节序列变体来显示转录或RNA稳定性改变的证据，并在人群（单倍型结构）（单倍型结构）中建立这些变体之间的关联，并测试那些识别与T2DM，胰岛素抵抗和胰岛素抗性和无序的绝缘素的鉴定这些单倍型的变体。目前只提出了AIM 1的研究，并将寻求收集可用于为NIH申请的试点数据，以提供足够的资金来进行拟议的研究。这项工作最终将确定可能提供药物靶标的潜在遗传变异，或者是识别旨在改变ERSR基因转录的药物中受益的个体的方法。因此，这项工作有可能直接影响T2DM和代谢综合征的预防和护理。