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

描述（由申请人提供）：秀丽隐杆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（GSCs）数量的减少通过不同于与营养可利用性和生长信号相关的途径增加了寿命和抗逆性，并且可能是保守的。GSC长寿途径可能在逆境中保持生殖能力，我们推测它也可能防御与过度的体细胞蛋白质和脂质生产相关的压力，否则将致力于生殖。GSC通路涉及脂质代谢、自噬和蛋白酶体活性的改变。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在肠道（肝脏、脂肪、胰腺对应物）中起作用。关于这种信号传导是如何工作的，以及GSC长寿途径是如何增加寿命和抗逆性的，还有很多有待研究。对GSC通路的理解对人类健康具有重要的影响和广泛的意义，因为它提供了1)一个新的窗口，了解组织对长寿保证机制的非自主调节，以及2)一个例子，说明生殖细胞或干细胞群体如何将其状态传达给维持它的“生态位”组织。我们未发表的研究结果表明，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， SKN-1是延长寿命和抗逆性所必需的。SKN-1提供了一个非常有利的机会，通过筛选来探索GSC通路的调节，并确定该通路如何促进长寿和健康。本项目将采用RNA干扰（RNAi）筛选参与SKN-1调控的基因来阐明GSC通路的调控机制。它还将研究我们的模型，即GSC通路涉及我们已经确定的两个“新”SKN-1功能，这些功能在分泌应激条件下可能很重要：蛋白质平衡维持和脂质代谢调节。最后，该项目将采用RNAseq表达谱来鉴定受SKN-1调节的基因和过程，以响应GSC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通路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缺失的代谢和生物过程，以及阐明GSC通路在组织间和组织内调节SKN-1和其他因子的机制。该结果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。

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 Our unpublished results indicate that the GSC longevity pathway regulates the conserved stress defense and longevity factor SKN-1/Nrf in the intestine and that SKN-1 is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.