Inositol signaling in C. elegans Senescence and Diapause

线虫衰老和滞育中的肌醇信号传导

• 批准号: 9904320
• 负责人: GARY B RUVKUN
• 金额: $ 47.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904320
• 关键词: Adaptor Signaling Protein; Affect; Aging; Animals; Applications Grants; Behavior; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Binding; Biotin; Caenorhabditis elegans; Cell physiology; Cells; Cellular Structures; Cellular biology; Chemicals; Chimeric Proteins; Code; Collection; Complex; Coupled; Couples; Coupling; Defect; Development; Diapause; Drug Metabolic Detoxication; Elongation Factor; Endocrine; Endocrine system; Environment; Enzymes; Escherichia coli; Eukaryota; Female; Fetal Development; Gene Expression Profile; Gene Silencing; Genes; Genetic study; Grant; Homologous Gene; Human; Immune; Immunity; Influentials; Inositol; Insulin; Intestines; KSR gene; Knock-out; Legionella pneumophila; Length; Ligase; Liver; Longevity; MAP Kinase Kinase Kinase; MEKs; Mammals; Measures; Microbe; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular Machines; Monitor; Mus; Muscle; Mutation; Neurons; Nuclear; Nuclear Hormone Receptors; Pathway interactions; Pattern; Peptides; Perch; Pharmaceutical Preparations; Phosphotransferases; Point Mutation; Poisoning; Process; Proteins; Proteomics; RNA interference screen; Regulation; Ribosomal Proteins; Ribosomes; Signal Pathway; Signal Transduction; Sirolimus; Streptavidin; System; Testing; Tissues; Toxin; Translations; Up-Regulation; Variant; Virulence Factors; Work; alpha Toxin; assault; base; blind; cell type; cholinergic; dopaminergic neuron; drug sensitivity; experimental study; fusion gene; gene product; genetic analysis; genome-wide; healthspan; human female; human male; inhibitor/antagonist; insulin-like signaling; male; microbial; microbiome; microbiota; multicatalytic endopeptidase complex; mutant; pathogenic bacteria; programs; promoter; proto-oncogene protein pim; receptor; receptor function; response; ribosome profiling; sarcopenia; senescence; small molecule; transcription factor; translation factor; whole genome

Project Summary Abstract: During the last 20 years, the insulin-like/daf-2 signaling pathway has emerged from genome-wide RNAi screens as the most potent regulator of lifespan in C. elegans; it is a significant aging axis in mammals as well. Our full genome screens for lifespan regulatory processes have also revealed that the second rank of longevity regulation surveils core components of cells, for example, the ribosome, and if deficits are detected, couples to an endocrine system of immunity and longevity control that is distinct from the insulin-like pathway. In fact, detoxification pathways are coupled to lifespan regulation in mice as well. The remarkable ability of rapamycin to extend the lifespan of mice is likely to be based on its ability to engage this surveillance/longevity control system. Eukaryotes live in microbe-rich environments and are continuously challenged by microbial attacks. In the past grant cycle we have greatly expanded our genetic analysis of how C. elegans, and we believe that eventually this will be shown to apply across all eukaryotes, surveils its core cellular components, most especially in this grant, the ribosome, for attacks and signals such attacks to innate immune and detoxification responses as well as to longevity programs. We were initially drawn to these experiments by our work on regulation of longevity and our finding that gene inactivations of core cellular processes such as translation potently induce increased longevity. The major activity of this grant proposal is to test whether the many mutants we have isolated which either inappropriately activate detoxification pathways or fail to activate such pathways have consequences on the lifespan and measures of aging of the animal. The coupling of longevity control to detoxification and immunity provides a satisfying explanation for why human females live longer than males: we hypothesize that females have a higher set point for detoxification to protect the fragile developing fetus. Variation in these same pathways will reveal how humans respond appropriately and inappropriately to drugs or bacterial pathogens, or activate drug detoxification pathways in the absence of a triggering drug, perhaps inducing a false endocrine state of poisoning. Our proposal to study how the microbial flora attempt to subvert these pathways will also reveal how variation in the microbiome may underlie variation in human longevity.

项目摘要摘要： 在过去的20年中，胰岛素样/DAF-2信号通路已从全基因组RNAi中出现 屏幕是秀丽隐杆线虫中最有效的寿命调节器；它是哺乳动物中的重要衰老轴 出色地。我们用于寿命调节过程的完整基因组筛选也表明 寿命调节监测细胞的核心成分，例如核糖体，如果检测到缺陷， 伴侣与与胰岛素样途径不同的免疫和寿命控制的内分泌系统。 实际上，排毒途径也与小鼠的寿命调节耦合。显着的能力 雷帕霉素可以延长小鼠的寿命，这可能是基于其参与的能力 监视/寿命控制系统。真核生物生活在微生物丰富的环境中，并且不断 受微生物攻击的挑战。在过去的赠款周期中，我们大大扩展了我们对 秀丽隐杆线虫如何，我们认为最终将证明这将在所有真核生物中施加 核心细胞组件，尤其是在这笔赠款的核糖体中，用于攻击和信号，以下攻击 先天免疫和排毒反应以及对寿命计划的反应。我们最初被吸引到 这些实验是通过我们对寿命调节的工作以及核心基因失活的发现 诸如翻译等细胞过程有效诱导寿命的增加。这笔赠款的主要活动 建议是测试我们已经隔离的许多突变体是否适当激活 解毒途径或无法激活此类途径会影响寿命和措施 动物衰老。寿命控制与排毒和免疫力的耦合提供了令人满意的 解释为什么人类女性的寿命比男性更长：我们假设女性有更高的场景 排毒的点保护易碎的胎儿。这些相同途径的变化将显示 人类如何对药物或细菌病原体做出适当和不适当的反应，或激活药物 在没有触发药物的情况下排毒途径，也许会诱导错误的内分泌状态 中毒。我们研究微生物菌群尝试颠覆这些途径的建议也将揭示 微生物组的变化如何构成人类寿命的变化。