Glial regulation of longevity through a transcellular unfolded protein response

胶质细胞通过跨细胞未折叠蛋白反应调节寿命

• 批准号: 9902280
• 负责人: Andrew G Dillin
• 金额: $ 39.25万
• 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: 2018-07-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902280
• 关键词: Age; Age of Onset; Aging; Animals; Atherosclerosis; Biological Models; Brain; Caenorhabditis elegans; Candidate Disease Gene; Cells; Chronic; DNA Sequence Alteration; DNA sequencing; Data; Defect; Degenerative Disorder; Dense Core Vesicle; Dependence; Diabetes Mellitus; Distal; Ectopic Expression; Electron Microscopy; Endoplasmic Reticulum; Exhibits; Exposure to; Flow Cytometry; Genes; Genetic; Genetic Epistasis; Genetic Screening; Genetic Transcription; Health; Human; Impairment; Infection; Intestines; Laboratories; Longevity; Malignant Neoplasms; Mediating; Metabolic Diseases; Microscopic; Molecular; Molecular Chaperones; Morphology; Mutagenesis; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Nutrient; Obesity; Onset of illness; Organism; Peripheral; Physiological; Play; Proteins; Proteome; RNA Interference; RNA interference screen; Regulation; Resistance; Role; Signal Transduction; Signaling Molecule; Source; Stress; Structure; Suppressor Genes; Techniques; Technology; Therapeutic; Time; Tissues; Translations; Vesicle; Whole Organism; base; biological adaptation to stress; cell type; deep sequencing; endoplasmic reticulum stress; experimental study; misfolded protein; mutant; neurotransmission; new therapeutic target; particle; prevent; promoter; protein aggregation; protein misfolding; proteostasis; response; ribosome profiling; stressor; tool; trafficking; transcription factor; transcriptome sequencing; whole genome

Cells are repeatedly exposed to various stressors that disrupt protein homeostasis (such as infection, excess nutrients, heat, genetic mutations), resulting in protein misfolding and aggregation. To maintain protein homeostasis (proteostasis), cells have evolved compartment specific stress responses such as the Unfolded Protein Response of the endoplasmic reticulum (UPRER). In times of ER stress when the load of misfolded or unfolded proteins overwhelms the ER, the UPRER is initiated to restore proteostasis. Unfortunately, the ability to mount an effective UPRER is impaired with age, which likely contributes to the accumulation of misfolded proteins - a central molecular hallmark of aging and many degenerative diseases. Our laboratory discovered that ectopic expression of the UPRER transcription factor xbp-1s in neurons is sufficient to prevent age-onset loss of UPRER throughout the organism. Surprisingly, neuronal expression of xbp-1s leads to cell non-autonomous activation of the UPRER in distal, intestinal cells and extends lifespan in C. elegans. Initially this phenomenon was ascribed only to neurons, however recent data from our lab suggests glial cells are more potent cell non-autonomous regulators of ER stress resistance and longevity. Animals lacking a subtype of glial cell are more susceptible to chronic ER stress. Conversely, expressing xbp-1s in glia results in robust ER stress resistance and lifespan extension in a mechanism that is distinct from that initiated by neuronal xbp-1s. Therefore, we hypothesize that glial cells play a central role in coordinating organismal ER stress resistance and longevity. In this proposal, we outline our strategy to pinpoint the origin and identity of the glial cell non-autonomous signal (Aim 1) and to uncover the mechanism by which the signal is perceived in distal tissues (Aim 2). Our approach utilizes techniques which combine the traditional advantages of using C. elegans as a model system (genetic tractability, transparency, short lifespan), with advanced technologies (large particle flow cytometry and tissue-specific ribosomal profiling) to study cell non-autonomous signaling between tissues in the context of aging. Data generated through this proposal will implicate glia as cell non-autonomous regulators of aging and open new avenues for metabolic and neurodegenerative disease therapeutics.

细胞反复暴露于破坏蛋白质稳态的各种应激源（如感染， 过量的营养、热量、基因突变），导致蛋白质错误折叠和聚集。为了维持蛋白质 在体内平衡（蛋白质平衡）的情况下，细胞已经进化出隔室特异性应激反应，例如未折叠的 内质网的蛋白质反应（UPRER）。在ER应力的时候，当错误折叠或 当未折叠的蛋白质使ER变小时，启动UPRER以恢复蛋白质稳态。 不幸的是，随着年龄的增长，有效的UPRER的能力受到损害，这可能有助于 错误折叠蛋白质的积累-衰老和许多退行性疾病的中心分子标志。 我们的实验室发现，在神经元中UPRER转录因子xbp-1s的异位表达是足够的， 以防止整个生物体中UPRER的老化损失。令人惊讶的是，XBP-1s的神经元表达导致 细胞非自主激活的UPRER在远端，肠细胞和延长寿命的C。优雅的 最初，这种现象仅归因于神经元，但我们实验室的最新数据表明，神经胶质细胞 细胞是ER应激抗性和寿命的更有效的细胞非自主调节剂。动物缺乏A 胶质细胞亚型对慢性ER应激更敏感。相反，在神经胶质细胞中表达xbp-1s会导致 强大的ER应激抵抗和寿命延长的机制，这是不同于神经元启动的机制， xbp-1s。因此，我们推测胶质细胞在协调机体内质网应激中起着重要作用 抵抗力和寿命。在这个建议中，我们概述了我们的战略，以查明胶质细胞的起源和身份， 细胞非自主信号（目的1），并揭示该信号在远端感知的机制， 组织（目标2）。我们的方法利用的技术，联合收割机的传统优势，使用C。elegans 作为一个模型系统（遗传易处理性，透明度，寿命短），具有先进的技术（大颗粒 流式细胞术和组织特异性核糖体分析）来研究组织之间的细胞非自主信号传导 in the context背景of aging老化.通过该提案生成的数据将表明神经胶质是非自主细胞 调节剂的老化和开辟新的途径，代谢和神经退行性疾病的治疗。