Insulin networks in aging and obesity

胰岛素/IGF-1信号通路在调节衰老过程和衰老相关疾病中起着重要作用。在线虫中，秀丽隐杆线虫和哺乳动物一样，IIS通路除了调节寿命外，还调节新陈代谢、生长和发育。虽然秀丽隐杆线虫只有一个胰岛素/IGF-1受体，但线虫基因组测序项目显示有40个胰岛素样肽。迄今为止，这些肽的功能在很大程度上仍然未知。这一建议使用秀丽隐杆线虫作为模型系统来揭示胰岛素样肽网络如何调节寿命。秀丽隐杆线虫是这些研究的首选生物，因为蠕虫的寿命短，可复制，而且由于许多可用的资源和技术，系统方法是可行的。假设胰岛素肽的差异表达和组合功能是寿命的主要决定因素。系统方法是唯一适合解决这一假设的方法。在Aim 1中，含有胰岛素启动子的转基因蠕虫菌株：40个胰岛素基因的GFP融合构建体将通过光镜视觉分析基因的时空表达，并使用称为Nanostring （nCounter）的敏感mRNA数字分析技术进行量化。在Aim 2中，将分析相关代谢和环境条件下GFP的时空表达和所有40个胰岛素基因的mRNA定量。最后，在Aim 3中，胰岛素样肽的剂量将被调节，以确定对

The insulin/IGF-1 signaling (IIS) pathway plays a fundamental role in regulation of the aging process and age-related disease. In the nematode, C. elegans, as with mammals, the IIS pathway modulates metabolism, growth and development in addition to life span. Although in C. elegans there is a single insulin/IGF-1 receptor, the C. elegans genome sequencing project revealed that there are 40 insulin- like peptides. To date, the function of these peptides remains largely unknown. This proposal uses C. elegans as a model system to uncover how insulin-like peptide networks modulate life span. C. elegans is an organism of choice for these studies since worms have a short, reproducible life span, and because systems approaches are feasible due to many available resources and techniques. The hypothesis is that differential expression and combinatorial function of insulin peptides is a major determinant of life span. Systems approaches are uniquely suited to address this hypothesis. In Aim 1, transgenic worm strains harboring insulin promoter:GFP fusion constructs for each of the 40 insulin genes will be visually analyzed for spatiotemporal gene expression by light microscopy and quantified using sensitive mRNA digital profiling technology called Nanostring (nCounter). In Aim 2, spatiotemporal expression of GFP and mRNA quantification of all 40 insulin genes will be analyzed under relevant metabolic and environmental conditions. Finally, in Aim 3, dosage of the insulin like peptides will be modulated to determine the effect on lifespan and fat metabolism. Data will then be integrated into a network that will provide the firs comprehensive analysis of insulin peptides in a metazoan organism and will result in greater into how insulin/IGF-1 signaling achieves specificity to regulate aging and age-related diseases.