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: 8716631
• 负责人: T Keith Blackwell
• 金额: $ 24.9万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716631
• 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的机制的一个强大的模型。在线虫中，生殖系干细胞(GSCs)数量的减少通过一种不同于与营养可获得性和生长信号相关的途径来增加寿命和抗逆性，并且可能是保守的。GSC长寿途径可能会在逆境中保持生殖能力，我们推测它也可能防御与过度的躯体产生蛋白质和脂肪相关的压力，否则这些蛋白质和脂肪将致力于生殖。GSC途径涉及脂类代谢、自噬和蛋白酶体活性的变化。它是通过复杂的器官间信号网络介导的，需要长寿因子DAF-16/FoxO作用于肠道(肝脏、脂肪、胰腺)。关于这一信号是如何工作的，以及GSC长寿途径如何延长寿命和抗逆性，仍有许多有待了解。对GSC途径的理解对人类健康具有高度的影响和广泛的意义，因为它提供了一个新的窗口，可以了解组织对长寿保证机制的非自主调节，以及2)一个细菌或干细胞群体如何将其状态传达给维持它的“生态位”组织的例子。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是导致寿命和应激抗性增加所必需的。SKN-1提供了一个非常有利的机会，通过筛选来探索GSC途径的调控，并确定该途径如何促进长寿和健康。本项目将利用RNA干扰(RNAi)筛选参与其调控SKN-1的基因，以阐明GSC途径的调控机制。它还将研究我们的模型，即GSC途径涉及两个我们已经确定的在分泌应激条件下可能重要的“新的”SKN-1功能：维持蛋白稳定和调节脂质代谢。最后，该项目将使用RNAseq表达谱来识别受SKN-1调控的基因和过程，以响应GSC的缺失。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和其他参与GSC途径的转录因子之间可能的功能相互作用，确定SKN-1调节的基因如何参与响应GSC缺失而调节的代谢和生物过程，以及阐明GSC途径跨组织和在组织内调节SKN-1和其他因子的机制。这些结果很可能广泛适用于理解调节寿命的过程或协调影响生物体衰老的组织之间的通信。