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）：秀丽隐杆线虫是发现影响衰老的机制的强大模型。在秀丽隐杆线虫中，种系干细胞数量（GSC）的减少可通过与养分可用性和生长信号相关的途径提高寿命和抗压力性，并且可以保守。 GSC寿命途径可能会在逆境中保留生殖能力，我们推测它也可以抵御与蛋白质过多的蛋白质和脂质相关的压力，否则该蛋白质和脂质否则将承诺繁殖。 GSC途径涉及脂质代谢，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，需要在肠道（肝，脂肪，胰腺对应物）中作用的寿命因子DAF-16/FOXO。关于这种信号的工作原理以及GSC寿命途径如何增加寿命和压力抵抗力还有很多待了解。对GSC途径的理解对人类健康具有很高的影响和广泛的意义，因为它提供了一个新颖的窗口，以进行组织非自治的寿命保证机制调节，以及2）一个例子，说明了细菌或干细胞种群如何将其状态传达给维持它的“利基”组织。我们未发表的结果表明，GSC的寿命途径调节肠中保守的应力防御和寿命因子SKN-1/NRF，并且SKN-1对于寿命和抗压力抗性的增加都是必需的。 SKN-1为通过筛选提供了一个非常有利的机会来探测GSC途径调节，并确定该途径如何促进寿命和适应性。该项目将采用RNA干扰（RNAI）筛选，以调节其SKN-1的基因以阐明GSC途径调节机制。它还将研究我们的模型，GSC途径涉及我们确定的两个“新” SKN-1功能，它们在分泌压力的条件下可能很重要：维持蛋白质的脂质代谢和调节。最后，该项目将采用RNASEQ表达分析来识别SKN-1对GSC缺失的调节的基因和过程。这个探索性的为期两年的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之间的可能功能相互作用以及GSC途径中涉及的其他转录因素，确定SKN-1调节的基因如何促进对GSC缺失的响应以及其他GSC跨越组织范围内的响应范围内的代谢和生物学过程。结果可能会广泛用于理解调节寿命或坐在影响生物体衰老的组织之间进行通信的过程。