Insulin networks in aging and obesity

衰老和肥胖中的胰岛素网络

• 批准号: 8513864
• 负责人: Ashlyn Dixon Ritter
• 金额: $ 3.04万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513864
• 关键词: Address; Affect; Age; Aging; Aging-Related Process; Attention; Biological; Biological Models; C. elegans genome; Caenorhabditis elegans; Categories; Chronic; Cues; Data; Development; Disease; Eating; Ensure; Exhibits; Family member; Foundations; Gene Expression; Gene Family; Genes; Genome; Glucose; Goals; Green Fluorescent Proteins; Growth; Growth and Development function; Heat Stress Disorders; Individual; Insulin; Insulin Signaling Pathway; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Intestines; Lead; Ligands; Link; Longevity; Mammals; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Microscopy; Molecular; Mutation; Nematoda; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Oxidative Stress; Pathway interactions; Pattern; Peptides; Phenotype; Phylogeny; Physiological; Physiological Processes; Play; Prevalence; Regulation; Research; Research Personnel; Resolution; Resources; Role; Signal Pathway; Signal Transduction; Specificity; Starvation; Stress; System; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Transgenic Animals; Transgenic Organisms; age related; biological adaptation to stress; combinatorial; detection of nutrient; digital; disorder risk; dosage; falls; genome sequencing; insight; light microscopy; lipid metabolism; loss of function; nano-string; paralogous gene; promoter; receptor; response; spatiotemporal; success

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.

胰岛素/IGF-1信号通路（IIS）在衰老过程和年龄相关疾病的调节中起着重要作用。在线虫中，C.与哺乳动物一样，秀丽隐杆线虫的IIS途径除了调节寿命外，还调节代谢、生长和发育。虽然在C. elegans存在单一的胰岛素/IGF-1受体，C. elegans基因组测序计划显示，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。该方案使用C。elegans作为一个模型系统来揭示胰岛素样肽网络如何调节寿命。C.线虫是这些研究的首选生物体，因为蠕虫的寿命短，可再生，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个假设。在目的1中，将通过光学显微镜视觉分析40个胰岛素基因中的每一个的携带胰岛素启动子：GFP融合构建体的转基因蠕虫菌株的时空基因表达，并使用称为Nanostring（nCounter）的敏感mRNA数字分析技术进行定量。在目标2中，将在相关代谢和环境条件下分析所有40种胰岛素基因的GFP时空表达和mRNA定量。最后，在目的3中，将调节胰岛素样肽的剂量以确定对胰岛素样肽的作用。 寿命和脂肪代谢。然后，数据将被整合到一个网络中，该网络将提供对后生动物生物体中胰岛素肽的第一次全面分析，并将导致更深入地了解胰岛素/IGF-1信号传导如何实现调节衰老和年龄相关疾病的特异性。