Insulin networks in aging and obesity

胰岛素/胰岛素样生长因子-1信号通路(IIS)在调节衰老过程和老年性疾病中起着重要作用。在线虫中，线虫和哺乳动物一样，IIS途径除了调节寿命外，还调节新陈代谢、生长和发育。虽然在线虫中只有一个胰岛素/IGF-1受体，但线虫基因组测序项目显示，有40个胰岛素样肽。到目前为止，这些多肽的功能在很大程度上仍不清楚。这项提案使用线虫作为模型系统来揭示胰岛素样肽网络是如何调节寿命的。线虫是这些研究的首选生物体，因为蠕虫的寿命短，可重复，而且由于有许多可用的资源和技术，系统方法是可行的。假设胰岛素多肽的差异表达和组合功能是决定寿命的主要因素。系统方法是唯一适合解决这一假设的方法。在目标1中，40个胰岛素基因中每一个都含有胰岛素启动子：GFP融合结构的转基因蠕虫株将通过光学显微镜对时空基因表达进行可视化分析，并使用名为纳米串(NCounter)的敏感mRNA数字图谱技术进行定量。在目标2中，将分析在相关代谢和环境条件下绿色荧光蛋白的时空表达和所有40个胰岛素基因的mRNA定量。最后，在目标3中，胰岛素样肽的剂量将被调节以确定对 寿命和脂肪代谢。然后，数据将被整合到一个网络中，该网络将首次对后生生物中的胰岛素肽进行全面分析，并将导致更多关于胰岛素/IGF-1信号如何实现调节衰老和年龄相关疾病的特异性的研究。

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.