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： 在过去的20年中，胰岛素样/daf-2信号通路已经从全基因组RNAi中出现 筛选出C.它是哺乳动物中重要的衰老轴， 好.我们对寿命调节过程的全基因组筛选也显示， 寿命调节监视细胞的核心组分，例如核糖体，并且如果检测到缺陷， 与免疫和长寿控制的内分泌系统相结合，该内分泌系统与胰岛素样途径不同。 事实上，解毒途径也与小鼠的寿命调节有关。的神通 雷帕霉素延长小鼠寿命的能力可能是基于它能够参与这一过程。 监控/寿命控制系统。真核生物生活在微生物丰富的环境中， 受到微生物攻击的挑战在过去的资助周期中，我们极大地扩展了我们的遗传分析， 如何C。我们相信，最终这将被证明适用于所有真核生物，监测其 核心细胞成分，特别是在这个赠款，核糖体，攻击和信号，这种攻击， 先天免疫和解毒反应以及长寿计划。我们最初被吸引到 这些实验是通过我们对长寿调节的研究以及我们发现核心基因的失活 诸如翻译的细胞过程有效地诱导增加的寿命。这项赠款的主要活动 我们的建议是测试我们分离出的许多突变体是否会不适当地激活 解毒途径或未能激活这种途径会对寿命产生影响， 动物的衰老。长寿控制与解毒和免疫的耦合提供了一个令人满意的 解释为什么人类女性比男性长寿：我们假设女性有更高的 排毒点，以保护脆弱的发育中的胎儿。这些相同途径的变异将揭示 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 解毒途径在没有触发药物的情况下，可能会诱导一种虚假的内分泌状态， 中毒我们研究微生物植物群如何试图破坏这些途径的提议也将揭示 微生物组的变化如何成为人类寿命变化的基础。