Inositol signaling in C. elegans Senescence and Diapause

线虫衰老和滞育中的肌醇信号传导

基本信息

批准号：
8387449
负责人：
GARY B RUVKUN
金额：
$ 52.04万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8387449
关键词：
1-Phosphatidylinositol 3-Kinase Adipose tissue Affect Age Aging Alleles Animals Backcrossings Biological Assay Biological Models Caenorhabditis elegans Candidate Disease Gene Cell Culture Techniques Cell Nucleus Cells Cellular Stress Cellular Structures Chimeric Proteins Coupled Couples Cytoskeleton Defect Detection Development Diabetes Mellitus Diapause Drosophila genus Eating Elements Endocrine Endocrine system Essential Genes Gene Silencing Genes Genetic Genetic Screening Genome Hormonal Human IGF1 gene Induced Mutation Inositol Insulin Insulin Signaling Pathway Length Life Liver Longevity Longevity Pathway Mammals Maps Mass Spectrum Analysis Mediating Medical Metabolic Control Metabolism MicroRNAs Mitochondria Modeling Molecular Monitor Muscle Mutation Neuroendocrine Cell Neuropeptides PTEN gene Pancreas Pathway interactions Pattern Phenotype Phosphotransferases Physiological Process Proteins Proteomics Proto-Oncogene Proteins c-akt Protocols documentation RNA Interference Regulation Reporter Genes Rest Ribosome Inactivation Ribosomes Screening procedure Sentinel Signal Pathway Signal Transduction Single Nucleotide Polymorphism Map Small Interfering RNA Small RNA Stress Surveys System Testing Tissues Translations Tumor Suppressor Proteins Validation Variant Whole Organism Xenobiotics animal extract cell type drug sensitivity feeding functional genomics fusion gene genetic analysis genome-wide human tissue inhibitor/antagonist insulin signaling late disease onset longevity gene mutant normal aging promoter receptor relating to nervous system reproductive response senescence tissue culture transcription factor

项目摘要

DESCRIPTION (provided by applicant): An insulin-like signaling pathway is the most potent regulator of lifespan in C. elegans. The function of this pathway in mediating metabolism and aging is conserved in C. elegans, Drosophila, and mammals. Because so much of the insulin signaling pathway is conserved, the new components we discover in C. elegans will have broad relevance to mammalian insulin signaling and longevity control. Genetic analysis in C. elegans continues to identify components of the pathway that are likely to reveal human variation in insulin-like signaling, with medical significance for diabetes and the understanding of how insulin signaling and analogous hormonal pathways couple chronological age to many late onset diseases. Using RNAi to screen for defects in daf-2 pathway mediated longevity regulation, we identified a comprehensive genetic network necessary for the longevity response to low daf-2 insulin/IGF1 signaling (9). Similarly, our proteomic analysis of insulin signaling components in Aim 2 has identified other new and unstudied candidate genes to act in insulin signaling. The use of RNAi screens and proteomics in C. elegans is opportune for two reasons: first, the tissues where insulin signaling is key for metabolic control has changed dramatically over the past decade. No longer is an exploration of insulin signaling only in the liver or muscle or even pancreas definitive. Neural and adipose centers of insulin signaling have emerged (7). We have identified new protein components of insulin signaling from whole animal extracts, and our RNAi screens are done in the whole animal, so insulin signaling across tissues is surveyed. This is unlike mammalian insulin signaling functional genomics which may assay for insulin responses in tissue culture, but not in the physiological context of a whole organism. Aging and diabetes may be more physiological and endocrine, not easily modeled in cell culture. In this way, the C. elegans insulin signaling genetic system is better model system for human aging and human diabetes than human cell culture. Our full genome screens for lifespan regulatory processes have also revealed that the second most potent axis of longevity regulation surveys core components of cells, the ribosome, the mitochondrion, the cytoskeleton, and if deficits are detected, the pathway couples to an endocrine system of longevity control that is distinct from the insulin-like pathway. Our exploration of the endocrine system for surveillance and signaling of deficits in core cellular components promises to illuminate an entirely new axis of eukaryotic lifespan regulation. Variation in both these endocrine systems may underlie human lifespan variation as well as variation in metabolism and drug sensitivities. PUBLIC HEALTH RELEVANCE: An insulin-like signaling pathway regulates metabolism and aging in C. elegans, Drosophila, and mammals. Our genetic, proteomic, and functional genomic analysis in C. elegans continues to identify components of the pathway with medical significance for diabetes and the understanding of how insulin signaling and analogous hormonal pathways couple chronological age to many late onset diseases. We will also explore another endocrine pathway for longevity that is coupled to the surveillance of core cellular elements such as the ribosome and mitochondrion.

描述（由申请人提供）：类似胰岛素的信号通路是秀丽隐杆线虫中最有效的寿命调节剂。在秀丽隐杆线虫，果蝇和哺乳动物中，该途径在介导代谢和衰老中的功能是保守的。由于许多胰岛素信号通路都是保存的，因此我们在秀丽隐杆线虫中发现的新组件将与哺乳动物胰岛素信号传导和寿命控制具有广泛的相关性。秀丽隐杆线虫中的遗传分析继续确定可能揭示人类类似胰岛素的信号变化的途径的组成部分，对糖尿病具有医学意义以及对胰岛素的理解信号传导和类似的荷尔蒙途径将年代年龄与许多晚期疾病息息相关。使用RNAi筛选DAF-2途径介导的寿命调节中的缺陷，我们确定了对低DAF-2胰岛素/IGF1信号的寿命响应所必需的综合遗传网络（9）。同样，我们对AIM 2中胰岛素信号成分的蛋白质组学分析已经确定了其他新的和未研究的候选基因，以在胰岛素信号传导中起作用。在秀丽隐杆线虫中使用RNAi筛选和蛋白质组学是有两个原因的：首先，在过去的十年中，胰岛素信号传导是代谢控制的关键的组织发生了巨大变化。不再仅在肝脏或肌肉甚至胰腺确定性中对胰岛素信号传导的探索。胰岛素信号的神经和脂肪中心已经出现（7）。我们已经确定了整个动物提取物的胰岛素信号传导的新蛋白质成分，并且我们的RNAi筛选是在整个动物中进行的，因此对跨组织进行了胰岛素信号传导。这与哺乳动物胰岛素信号传导功能基因组学不同，这可能分析组织培养中胰岛素反应，但在整个生物体的生理环境中却不是。衰老和糖尿病可能更生理和内分泌，不容易在细胞培养中建模。通过这种方式，秀丽隐杆线虫胰岛素信号遗传系统比人类细胞培养更好的是人类衰老和人类糖尿病的模型系统。 Our full genome screens for lifespan regulatory processes have also revealed that the second most potent axis of longevity regulation surveys core components of cells, the ribosome, the mitochondrion, the cytoskeleton, and if deficits are detected, the pathway couples to an endocrine system of longevity control that is distinct from the insulin-like pathway.我们对核心细胞成分缺陷的监视和信号的内分泌系统的探索有望阐明一个全新的真核寿命调节轴。这两种内分泌系统的变化都可能是人类寿命变化以及代谢和药物敏感性的变化。公共卫生相关性：一种类似胰岛素的信号通路可调节秀丽隐杆线虫，果蝇和哺乳动物的新陈代谢和衰老。我们在秀丽隐杆线虫中的遗传，蛋白质组学和功能基因组分析继续鉴定具有糖尿病具有医学意义的途径成分，以及对胰岛素信号传导和类似激素途径的理解与许多晚期发作疾病的年龄段。我们还将探索另一种寿命内分泌途径，该途径与核心细胞元素（如核糖体和线粒体）的监视相结合。