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

胶质细胞对内质网未折叠蛋白反应的细胞非自主信号传导

• 批准号: 10398380
• 负责人: Melissa G Metcalf
• 金额: $ 3.75万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398380
• 关键词: Address; Age of Onset; Aging; Animal Model; Applications Grants; Atherosclerosis; Award; Biology; Caenorhabditis elegans; Cells; Cellular Stress Response; Defect; Diabetes Mellitus; Distal; Endoplasmic Reticulum; Genetic; Heat shock proteins; Invertebrates; Investigation; Longevity; Malignant Neoplasms; Mammals; Mediator of activation protein; Metabolic; Metabolic Diseases; Molecular; Mus; Mutagenesis; Neurodegenerative Disorders; Neuroglia; Neurons; Obesity; Onset of illness; Organ; Organism; Parents; Pathway interactions; Peripheral; Phenotype; Process; Proteins; Proteome; Research; Resistance; Signal Transduction; Stress; Therapeutic; Tissues; Up-Regulation; age related; biological adaptation to stress; endoplasmic reticulum stress; glial activation; improved; neurotransmission; normal aging; novel; overexpression; parent grant; proteotoxicity; response; therapeutic target; transcription factor; transcriptome

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.

项目摘要 父母补助金没有变化 在无脊椎动物和脊椎动物模式生物中，如C。有证据表明， 对应激反应途径的组织特异性操作可以系统地发出信号， 远端组织中的通路。一个组织中的隔室蛋白毒性应激可以传递到远端 组织和诱导内质网未折叠蛋白反应（UPRER）的遗传途径。 结果表明，C. elegans 导致未连接的外周组织中应激反应性UPRR的上调。虽然起源于 单一组织，这些操作似乎能够传播同步变化， 在多种组织和器官中的胁迫抗性表型。这种细胞的非自主反应 强化了这样的想法，即在多细胞生物体中，蛋白质应激的感知可以被传递， 在整个机体内系统性地反应。然而，这种信号传导所必需的遗传要求 机制仍然未知。 我们假设胶质细胞XBP-1诱导了一种跨组织信号传导机制，以协调生物体范围内的 应激反应，更长的寿命和改善的代谢状态。这项拨款建议旨在确定 细胞非自主UPRER的信号传导和感知神经胶质激活的遗传要求。从 目标1中使用的无偏诱变筛选，我们将鉴定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，我们提出了表征细胞自主和细胞非自主激活， UPRER来确定这些看似不同的通路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 衍生自UPRER激活，并可能发现新的细胞信号或异常感测的 UPRER机械。 这项建议解决了一个空白领域的细胞应激反应解剖如何这些途径是 系统性激活和交流。此外，这项研究将推动神经胶质细胞的新兴领域， 通过探索神经胶质细胞的神秘分子机制和功能后果， 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。 在哺乳动物中，细胞非自主信号可以增加寿命和抗应激能力。回答 在这个建议中描述的问题不仅对正常衰老有治疗意义，而且对年龄- 发病