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

基本信息

批准号：
10383697
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10383697
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

项目摘要

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压力源（例如感染，过量的营养，热量，基因突变），导致蛋白质错误折叠和聚集。维持蛋白质稳态（蛋白抑制），细胞已经进化出隔室特异性应力反应，例如展开内质网的蛋白质反应（Uprer）。在急诊室压力时，当货物折叠式错误时或展开的蛋白质压倒了ER，将升级器启动以恢复蛋白质的速度。不幸的是，随着年龄的增长，安装有效船长的能力受到损害，这可能有助于错误折叠蛋白的积累 - 衰老和许多退化性疾病的中心分子标志。我们的实验室发现，神经元中升级转录因子XBP-1的异位表达足够为了防止在整个生物体中年龄发作的兴趣。令人惊讶的是，XBP-1S的神经元表达铅在远端，肠道细胞中升级物的非自主激活，并在秀丽隐杆线虫中延长寿命。最初，这种现象仅归因于神经元，但是我们实验室的最新数据表明Glial 细胞是ER应力抗性和寿命的更有效的细胞非自主调节剂。缺乏动物神经胶质细胞的亚型更容易受到慢性ER应激的影响。相反，在Glia中表达XBP-1会导致具有与神经元所引发的机制不同的机制中强大的ER应力抗性和寿命扩展 XBP-1。因此，我们假设神经胶质细胞在协调生物ER应激中起着核心作用抵抗和寿命。在此提案中，我们概述了确定神经胶质的起源和身份的策略细胞非自主信号（AIM 1），并发现信号在远端感知的机制组织（AIM 2）。我们的方法利用了结合了使用C.秀隐杆菌的传统优势的技术作为模型系统（遗传障碍性，透明度，寿命短），具有先进的技术（大粒子流式细胞仪和组织特异性核糖体分析），研究细胞之间非自主信号在组织之间在衰老的背景下。通过此提案产生的数据将牵涉到神经胶质作为细胞非自主的衰老和开放新途径的代谢和神经退行性疾病疗法的调节剂。