Regulation of SKN-1/Nrf functions by germline stem cells

生殖干细胞对 SKN-1/Nrf 功能的调节

• 批准号: 8582847
• 负责人: T Keith Blackwell
• 金额: $ 20.74万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582847
• 关键词: Ablation; Affect; Aging; Animals; Autophagocytosis; Biological Process; Caenorhabditis elegans; Cell Count; Cells; Commit; Communication; Complex; Endoplasmic Reticulum; Fatty acid glycerol esters; Future; Genes; Genetic; Genetic Transcription; Germ Cells; Gonadal structure; Growth; HMGB1 Protein; Health; Heat Stress Disorders; Homeostasis; Human; Insulin; Insulin-Like Growth Factor I; Intestines; Invertebrates; Learning; Lipids; Lipoproteins; Liver; Longevity; Longevity Pathway; Maintenance; Mediating; Metabolism; Mitochondria; Modeling; Molecular Profiling; Natural regeneration; Nematoda; Nutrient; Organ; Organism; Oxidative Stress; Pancreas; Pathway interactions; Population; Process; Processed Genes; Production; Proteins; RNA Interference; Regulation; Regulatory Pathway; Reproduction; Resistance; Role; Signal Transduction; Stem cells; Stress; Testing; Tissues; Work; base; dietary restriction; endoplasmic reticulum stress; fitness; lipid metabolism; multicatalytic endopeptidase complex; neuronal cell body; novel; public health relevance; reproductive; response; screening; stem cell population; transcription factor

DESCRIPTION (provided by applicant): C. elegans is a powerful model for discovering mechanisms that influence aging. In C. elegans a reduction in the number of germline stem cells (GSCs) increases lifespan and stress resistance through a pathway that is distinct from those related to nutrient availability and growth signals, and may be conserved. The GSC longevity pathway may preserve reproductive capacity during adversity, and we speculate that it might also defend against stress associated with excess somatic production of proteins and lipids that would otherwise be committed to reproduction. The GSC pathway involves changes in lipid metabolism, autophagy, and proteasome activity. It is mediated through complex inter-organ signaling networks, and requires the longevity factor DAF-16/FoxO acting in the intestine (liver, fat, pancreas counterpart). Much remains to be learned about how this signaling works, and how the GSC longevity pathway increases lifespan and stress resistance. An understanding of the GSC pathway is of high impact and broad significance for human health because it provides 1) a novel window into tissue non-autonomous regulation of longevity assurance mechanisms, and 2) an example of how a germ or stem cell population communicates its status to "niche" tissues that sustain it. Our unpublished results indicate that the GSC longevity pathway regulates the conserved stress defense and longevity factor SKN-1/Nrf in the intestine and that SKN-1 is required for the resulting increases in both lifespan and stress resistance. SKN-1 provides a highly advantageous opportunity to probe GSC pathway regulation through screening, and to determine how this pathway promotes longevity and fitness. This project will employ RNA interference (RNAi) screening for genes involved in its regulation of SKN-1 to elucidate GSC pathway regulatory mechanisms. It will also investigate our model that the GSC pathway involves two "new" SKN-1 functions we have identified that may be important under conditions of secretory stress: proteostasis maintenance and regulation of lipid metabolism. Finally, the project will employ RNAseq expression profiling to identify genes and processes that are regulated by SKN-1 in response to GSC absence. This exploratory two-year project will make possible a number of exciting future studies, including investigating possible functional interactions among SKN-1, DAF-16, and other transcription factors involved in the GSC pathway, determining how SKN-1-regulated genes contribute to metabolic and biological processes that are modulated in response to GSC absence, and elucidating mechanisms through which the GSC pathway acts across and within tissues to regulate SKN-1 and other factors. The results are likely to be widely applicable to understanding processes that modulate longevity or coordinate communications among tissues that influence aging of the organism.

描述（由申请人提供）：线虫是发现影响衰老机制的强大模型。在秀丽隐杆线虫中，生殖系干细胞（GSC）数量的减少通过一条与营养可用性和生长信号相关的途径不同的途径延长寿命和抗应激能力，并且可能是保守的。 GSC长寿途径可能在逆境中保留生殖能力，我们推测它也可能抵御与体细胞过量产生蛋白质和脂质相关的压力，否则这些蛋白质和脂质将用于繁殖。 GSC 途径涉及脂质代谢、自噬和蛋白酶体活性的变化。它通过复杂的器官间信号网络介导，并且需要长寿因子 DAF-16/FoxO 在肠道（肝脏、脂肪、胰腺对应物）中发挥作用。关于这种信号传导如何发挥作用，以及 GSC 长寿途径如何延长寿命和抗压能力，还有很多东西有待了解。了解 GSC 通路对人类健康具有重大影响和广泛意义，因为它提供了 1) 一个了解长寿保证机制的组织非自主调节的新窗口，2) 生殖细胞或干细胞群如何将其状态传达给维持它的“利基”组织的一个例子。我们未发表的结果表明，GSC 长寿途径调节肠道中保守的应激防御和长寿因子 SKN-1/Nrf，并且 SKN-1 是导致寿命和应激抵抗力增加所必需的。 SKN-1 提供了一个非常有利的机会，可以通过筛选来探索 GSC 通路的调节，并确定该通路如何促进长寿和健康。该项目将采用RNA干扰（RNAi）筛选参与SKN-1调节的基因，以阐明GSC途径的调节机制。它还将研究我们的模型，即 GSC 途径涉及我们已经确定的两个“新”SKN-1 功能，这两个功能在分泌应激条件下可能很重要：蛋白质稳态维持和脂质代谢调节。最后，该项目将利用 RNAseq 表达谱来识别因 GSC 缺失而受 SKN-1 调节的基因和过程。这个为期两年的探索性项目将使许多令人兴奋的未来研究成为可能，包括调查 SKN-1、DAF-16 和 GSC 通路中涉及的其他转录因子之间可能的功能相互作用，确定 SKN-1 调节的基因如何促进因 GSC 缺失而调节的代谢和生物过程，并阐明 GSC 通路在组织间和组织内发挥作用以调节 SKN-1 和其他因子的机制。这些结果可能广泛适用于理解调节寿命或协调影响有机体衰老的组织之间的通信的过程。