Cell Non-Autonomous Signaling of the Unfolded Protein Response of the ER by Glial Cells

项目概要 家长补助金没有变化 在无脊椎动物和脊椎动物模型生物中，例如线虫和小鼠，证据强烈表明 应激反应途径的组织特异性操作可以系统地发出信号并诱导这些 远端组织中的通路。一个组织中的区室蛋白毒性应激可以传递到远端 组织并诱导内质网未折叠蛋白反应（UPRER）的遗传途径。我们有 研究表明，秀丽隐杆线虫中的神经元和胶质细胞过度表达 UPRER 转录因子 XBP-1 导致未连接的外周组织中应激反应性 UPRER 上调。虽然起源于 对于单个组织，这些操作似乎能够将同步变化传播到与年龄相关的和 跨多个组织和器官的应激抵抗表型。这种细胞非自主反应 强化了这样的观点：在多细胞生物体中，蛋白质应激的感知可以被传达并 在整个有机体中系统地做出反应。然而，这种信号传导所必需的遗传要求 机制仍不清楚。 我们假设神经胶质 XBP-1 诱导跨组织信号传导机制来协调整个生物体 压力反应、更长的寿命和改善的代谢状态。本拨款提案旨在确定 细胞非自主 UPRER 的信号传导和传感神经胶质激活的遗传要求。来自 目标 1 中使用的无偏诱变筛选，我们将识别细胞非自主的潜在介质 UPRER的诱导将为衰老和代谢紊乱提供潜在的治疗靶点。 此外，在目标 2 中，我们建议表征细胞自主和细胞非自主激活 UPRER 来确定这些看似不同途径的蛋白质组和转录组的差异 UPRER 激活。这些分析将阐明远端组织如何检测和响应神经胶质信号 源自 UPRER 激活，并有可能发现新的细胞信号或由 UPRER 机械。 该提案通过剖析这些途径如何解决细胞应激反应领域的空白 系统地激活和沟通。此外，这项研究将推动胶质细胞这一新兴领域的发展 通过探索神经胶质细胞的神秘分子机制和功能后果来研究生物学 发信号。展望未来，这项研究将为进一步研究遗传途径提供基础 细胞非自主信号传导可延长哺乳动物的寿命和抗应激能力。回答 该提案中描述的问题不仅对正常衰老有治疗意义，而且对年龄-衰老也有治疗意义。 发病疾病。

PROJECT SUMMARY No Changes to Parent Grant Within invertebrate and vertebrate model organisms, such as C. elegans and mice, evidence stronglysuggests that tissue-specific manipulations of stress response pathways can signal systemically and induce these pathways in distal tissues. Compartmental proteotoxic stress in one tissue can be communicated to distal tissues and induce genetic pathways of the endoplasmic reticulum unfolded protein response (UPRER).We have shown that both neuronal and glial overexpression of the UPRER transcription factor, XBP-1s, in C. elegans causes upregulation of the stress responsive UPRER in unconnected, peripheral tissue. While originating from a single tissue, these manipulations appear capable of propagating synchronous changes to age-related and stress resistance phenotypes across multiple tissues and organs. This cell non-autonomous response reinforces the idea that in a multi-cellular organism, the sensing of protein stress can be conveyed and responded systemically across the organism. However, the genetic requirements necessary for this signaling mechanism remain unknown. We hypothesize that glial XBP-1s induces a trans-tissue signaling mechanism to coordinate an organism-wide stress response, longer lifespan, and improved metabolic state. This grant proposal seeks to identify the genetic requirements for both signaling and sensing glial activation of the cell non-autonomous UPRER. From an unbiased mutagenesis screen used in Aim 1, we will identify potential mediators of the cell non-autonomous induction of the UPRER that will provide potential therapeutic targets for aging and metabolic disorders. Additionally, in Aim 2 we propose to characterize both cell-autonomous and cell non-autonomous activation of the UPRER to determine differences in the proteome and transcriptome of these seemingly distinctpathways of UPRER activation. These analyses will elucidate how a distal tissue can detect and respond to theglial signal deriving from UPRER activation, and potentially discover novel cellular signals or aberrations sensed by the UPRER machinery. This proposal addresses a gap in the field of cellular stress response by dissecting how these pathways are systemically activated and communicated. Additionally, this research will advance the emerging field of glial biology through exploration of the enigmatic molecular mechanisms and functional consequences of glial signaling. Moving forward, this research will provide a basis for further investigation into the genetic pathways of cell non-autonomous signaling that increase longevity and stress resistance in mammals. Answering the questions described in this proposal will have therapeutic implications not only for normal aging, but also age- onset diseases.