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

2型糖尿病是最常见的内分泌疾病，影响了超过6%的西方人口，发病率稳步上升。这种疾病是由基因决定的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中也有类似程度的表达。然而，胰岛素信号转导在这些细胞类型中的作用在很大程度上仍不清楚。为了确定胰岛素信号转导的作用，我们在小鼠中有条件地灭活了胰岛素受体基因，方法是将携带loxP侧翼胰岛素受体等位基因的小鼠与那些在溶菌酶M启动子控制下表达Cre重组酶的小鼠杂交。由此产生的髓系特异性胰岛素受体基因敲除小鼠表现出对转录因子低氧诱导因子-1α的靶基因的诱导大大减少，这两种反应都是对IPS和低氧刺激的反应。本研究的目的是探讨巨噬细胞胰岛素信号转导在血管生成因子如血管内皮生长因子调控中的作用，并在体内确定在糖尿病过程中髓系细胞胰岛素信号转导在视网膜新生血管形成中的作用。

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.