Defining the differential roles of insulin and IGF-1 receptors in vivo

2型糖尿病在世界范围内稳步增加，并伴有心血管疾病、肾病和视网膜病变等继发性影响。在这种疾病中，病理生理学的一个核心组成部分是胰岛素抵抗。在这里，胰岛素/IGF-1系统通过结合胰岛素并激活其信号级联发挥关键作用。胰岛素（IR）和IGF-1受体（IGF1R）在几个功能域上高度同源，并共享许多下游信号传导成分。虽然这两种配体都可以结合每种受体，但胰岛素和IGF-1具有显著不同的生理作用和作用。已经有许多尝试通过构建嵌合受体来解决胰岛素和IGF-1信号传导的差异，但未能确定其生理特异性的独特方面。因此，我假设在体内观察到的胰岛素和IGF-1之间的主要生理差异与产前和产后生活中受体的组织分布和表达时间的差异以及不同配体受体相互作用的性质有关。为此，我将创建在IGF1R位点表达IR或IR/IGF1R嵌合体的转基因小鼠，并对IGF1R和IR位点的嵌合受体进行相反的处理。使用嵌合受体将允许研究体内受体的细胞内和细胞外结构域之间的差异。这项工作将排除IR和IGF1R信号之间的差异，并将有助于了解它们在几种病理生理疾病中的特异性。

Type 2 diabetes is steadly increasing worldwide and is paralleled by secondary effects like cardiovascular diseases, nephro- and retinopathy. In this disorder, a central component of the pathophysiology is insulin resistance. Here, the insulin/IGF-1 system plays a crucial role by binding of insulin and allowing to activate its signaling cascade. The insulin (IR) and IGF-1 receptor (IGF1R) are highly homologous in several functional domains and share many downstream signaling components. Although both ligands can bind to each receptor, insulin and IGF-1 have remarkably different physiological roles and effects. A number of attempts have been made to address differences in insulin and IGF-1 signaling by construction of chimeric receptors but have failed to define the unique aspect of its physiological specificities. I therefore hypothesize that the major physiological differences observed in vivo between insulin and IGF-1 relate to differences in tissue distribution and timing of expression of the receptors during pre- and post-natal life, and the nature of the different ligand receptor interactions. To this end I will create transgenic mice which express IR or IR/IGF1R chimeras in the IGF1R locus and doing the converse for IGF1R and chimeric receptors in the IR locus. Using chimeric receptors will allow for investigation of the differences between the intra- and extracellular domains of the receptors in vivo. This work will rule out the differences between IR and IGF1R signaling and will help to understand their specificities in several pathophysiological diseases.