Mechanisms of insulin signal transduction in macrophages in the development of diabetic neovasculatization of the retina

巨噬细胞胰岛素信号转导在糖尿病视网膜新生血管形成中的机制

• 批准号: 21909678
• 负责人: Professor Dr. Jens Claus Brüning
• 金额: --
• 依托单位: Zentrum für Endokrinologie, Diabetologie und Präventivmedizin (ZEDP)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/21909678?language=en
• 关键词: Mechanisms; insulin; signal; transduction; macrophages

Type 2 diabetes mellitus represents the most common endocrine disease affecting more than 6% of western populations with steadily increasing prevalence. The disease is caused by a genetically determined and environmentally modified insulin resistance. Insulin receptors are not only expressed in the classical insulin target tissues such as skeletal muscle, liver and adipose tissue, but they are also found to a similar extent on granulocytes and macrophages. Nevertheless, the role of insulin signal transduction in these cell types remains largely unclear. To determine the role of insulin signal transduction here, we have conditionally inactivated the insulin receptor gene in mice by crossing mice carrying a loxP-flanked insulin receptor allele with those expressing the Cre recombinase under control of the lysozyme M promoter. Resulting myeloid lineage-specific insulin receptor knockout mice exhibit a largely reduced induction of target genes of the transcription factor hypoxiainducible factor (HIF)-1 α both in response to IPS and hypoxia stimulation. The goal of the present research proposal is to investigate the role of insulin signal transduction in macrophages in the regulation of angiogenetic factors like VEGF, and to determine in vivo the role of insulin signal transduction in myeloid cells with respect to the development of retinal neovascularization during the course of diabetes.

2型糖尿病是最常见的内分泌疾病，影响超过6%的西方人群，患病率稳步上升。这种疾病是由基因决定和环境修饰的胰岛素抵抗引起的。胰岛素受体不仅在经典的胰岛素靶组织如骨骼肌、肝脏和脂肪组织中表达，而且在粒细胞和巨噬细胞上也发现了类似程度的表达。然而，胰岛素信号转导在这些细胞类型中的作用仍然很大程度上不清楚。为了确定胰岛素信号转导的作用，在这里，我们有条件地灭活小鼠的胰岛素受体基因的交叉小鼠携带loxP-侧翼的胰岛素受体等位基因与那些表达Cre重组酶的溶菌酶M启动子的控制下。由此产生的髓系特异性胰岛素受体敲除小鼠在IPS和缺氧刺激下对转录因子缺氧诱导因子（HIF）-1 α靶基因的诱导作用大大降低。本研究的目的是探讨巨噬细胞中胰岛素信号转导在调节血管生成因子如VEGF中的作用，并确定在体内骨髓细胞中胰岛素信号转导在糖尿病过程中视网膜新生血管形成中的作用。