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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：
8525303
负责人：
GARY B RUVKUN
金额：
$ 49.15万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8525303
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 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 deep sequencing 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 screening 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.

描述(申请人提供)：胰岛素样信号通路是线虫寿命最有效的调节因素。该通路在调节新陈代谢和衰老方面的功能在线虫、果蝇和哺乳动物中是保守的。由于胰岛素信号通路的大部分是保守的，我们在线虫中发现的新成分将与哺乳动物的胰岛素信号和寿命控制具有广泛的相关性。线虫的遗传分析继续识别可能揭示人类胰岛素样信号变异的途径的组成部分，对糖尿病具有医学意义，并了解胰岛素是如何信号和类似的激素途径将年龄与许多晚发疾病联系在一起。使用RNAi筛选daf-2途径介导的长寿调节的缺陷，我们确定了一个全面的遗传网络，对于低daf-2胰岛素/IGF1信号的长寿反应是必要的(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过的候选基因在胰岛素信号中起作用。在线虫中使用RNAi筛选和蛋白质组学是合适的，原因有两个：第一，胰岛素信号对代谢控制至关重要的组织在过去十年中发生了巨大变化。对仅在肝脏、肌肉甚至胰腺中传递胰岛素信号的探索不再是决定性的。胰岛素信号的神经和脂肪中心已经出现(7)。我们已经从整个动物的提取物中识别出胰岛素信号的新蛋白质成分，我们的RNAi筛查是在整个动物中进行的，所以跨组织的胰岛素信号被调查。这不同于哺乳动物胰岛素信号功能基因组学，后者可以在组织培养中检测胰岛素反应，但不能在整个生物体的生理环境中进行检测。衰老和糖尿病可能更多的是生理和内分泌的，不容易在细胞培养中建模。因此，线虫胰岛素信号基因系统是比人类细胞培养更好的研究人类衰老和人类糖尿病的模型系统。我们对寿命调节过程的全基因组筛查也揭示了第二有效的长寿调节轴调查细胞的核心成分，核糖体、线粒体、细胞骨架，如果检测到缺陷，该途径耦合到与胰岛素样途径不同的长寿控制的内分泌系统。我们对核心细胞成分缺陷的内分泌系统的监测和信号传递的探索，有望照亮真核生物寿命调控的一个全新轴。这两个内分泌系统的变化可能是人类寿命变化以及新陈代谢和药物敏感性变化的基础。