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: 9755196
• 负责人: Melissa G Metcalf
• 金额: $ 4.09万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755196
• 关键词: Address; Age; Age of Onset; Aging; Animal Model; Applications Grants; Atherosclerosis; Binding; Biology; Caenorhabditis elegans; Cells; Cellular Stress Response; Data; Defect; Detection; Diabetes Mellitus; Diet; Dissection; Distal; Ectopic Expression; Endoplasmic Reticulum; Exposure to; Genes; Genetic; Genetic Screening; Genetic Transcription; Heat shock proteins; Hypothalamic structure; Intestines; Invertebrates; Investigation; Life; Liver; Longevity; Malignant Neoplasms; Mammals; Mediator of activation protein; Messenger RNA; Mesylates; Metabolic; Metabolic Diseases; Methods; Molecular; Molecular Chaperones; Mus; Mutagenesis; Neurodegenerative Disorders; Neuroglia; Neurons; Nutrient; Obesity; Onset of illness; Organ; Organelles; Organism; Pathway interactions; Peripheral; Phenotype; Physiological; Process; Proteins; Proteome; Quality Control; RNA Splicing; Reporter; Research; Resistance; Signal Pathway; Signal Transduction; Stress; Therapeutic; Tissues; Toxin; Translating; Translations; Up-Regulation; Work; age related; arm; biological adaptation to stress; endoplasmic reticulum stress; extreme temperature; follow-up; glial activation; improved; insight; misfolded protein; mutant; neurotransmission; normal aging; novel; overexpression; prevent; programs; proteostasis; proteotoxicity; response; ribosome profiling; therapeutic target; transcription factor; transcriptome; transmission process

PROJECT SUMMARY Within invertebrate and vertebrate model organisms, such as C. elegans and mice, evidence strongly suggests 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 distinct pathways of UPRER activation. These analyses will elucidate how a distal tissue can detect and respond to the glial 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.

项目总结 在无脊椎动物和脊椎动物模式生物中，如线虫和老鼠，有强有力的证据 提示对应激反应通路的组织特异性操作可以系统地发出信号并诱导 这些通路在远端组织中。一个组织中的间隔性蛋白毒性应激可以传递到 并诱导内质网未折叠蛋白反应(UPRER)的遗传途径。 我们的研究结果表明，在C。 秀丽导致未连接的外周组织中应激反应UPRER的上调。而当 这些操作起源于单个组织，似乎能够将同步变化传播到 多个组织和器官的年龄相关和抗应激表型。此单元格不是自治的 反应强化了这样一种观点，即在多细胞有机体中，蛋白质应激的感觉可以被传递 并在整个有机体中系统地做出反应。然而，这一点所需的遗传要求 信号机制仍不清楚。 我们假设，胶质细胞XBP-1s诱导了一种跨组织信号机制来协调 整个生物体的应激反应、更长的寿命和改善的代谢状态。这项拨款提案旨在 确定细胞非自主激活信号和感觉神经胶质细胞的遗传要求 UPRER。从AIM 1中使用的无偏向突变筛选，我们将确定细胞的潜在介体 非自主诱导UPRER将为衰老和代谢提供潜在的治疗靶点 精神错乱。此外，在目标2中，我们建议对细胞自治和细胞非自治进行表征 激活UPRER以确定这些看似不同的蛋白质组和转录组的差异 UPRER的激活途径。这些分析将阐明远端组织如何检测和响应 来自UPRER激活的神经胶质信号，并可能发现新的细胞信号或感觉到的像差 被UPRER的机器。 这项建议通过剖析这些途径是如何解决细胞应激反应领域的一个空白。 被系统地激活和传达。此外，这项研究将推动新兴领域的发展 探索神经胶质细胞神秘的分子机制和功能后果的神经胶质生物学 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。 增加哺乳动物寿命和抗逆性的细胞非自主信号。回答问题 这项提案中描述的问题不仅对正常衰老有治疗意义，而且对年龄也有影响- 发病的疾病。