Systemic Regulation of ER Proteostasis

内质网蛋白质稳态的系统调节

基本信息

批准号：
10396458
负责人：
Chung Yin Kimberly Tsui
金额：
$ 6.98万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396458
关键词：
Aging Biological Assay CRISPR screen Caenorhabditis elegans Cell Communication Cell Culture Techniques Cell Line Cells Cellular Stress Cellular Stress Response Chemistry Clustered Regularly Interspaced Short Palindromic Repeats Communication Detection Disease Distal Endoplasmic Reticulum Enzymes GRP78 gene Genes Glycoproteins Health Homeostasis Human Induced pluripotent stem cell derived neurons Intestines Knock-out Label Longevity Mediating Methods Microscopy Modeling Mus Neurons Organism Pathway interactions Pharmacology Phosphines Physiological Protein Glycosylation Proteins Proteome Quality Control Regulation Reperfusion Injury Reporter Resistance Role Signal Pathway Signal Transduction Signaling Molecule Stress Supplementation Techniques Testing Tissues Toxic effect Tunicamycin Up-Regulation Work biological adaptation to stress endoplasmic reticulum stress experience experimental study extracellular genome-wide glycosylation hepatoma cell improved in vivo induced pluripotent stem cell insight liquid chromatography mass spectrometry nerve stem cell novel novel strategies promoter protein folding protein metabolite protein misfolding proteostasis proteotoxicity response stressor sugar unpublished works

项目摘要

Abstract Proper activation of cellular stress response pathways allows cells to adapt and maintain homeostasis during stressful conditions. While these pathways are typically thought to be regulated within a cell, recent studies in mice and C. elegans suggest that cellular stress experience in certain cells can distally activate stress response in other tissues. For example, work from our lab have shown that neuronal activation of the endoplasmic reticulum Unfolded Protein Response (UPRER) induces UPRER in the intestine of C. elegans, promoting stress resistance and longevity. These findings clearly demonstrates the importance of systemic regulation of ER proteostasis in organismal health. However, the mechanisms and the signaling molecules underlying such inter-tissue regulation of ER proteostasis remain unknown. Our preliminary work has identified N-acetylglucosamine (GlcNAc), an essential metabolite for protein glycosylation, as a candidate signaling molecule for regulating ER proteostasis across cells. I propose to elucidate mechanisms by which GlcNAc is released by stressed cells and utilized by recipient cells, and to develop novel methods to examine in vivo tissue-to-tissue GlcNAc signaling using neuronal cell culture and C. elegans models. This work will uncover how GlcNAc regulates systemic ER proteostasis, and establish novel techniques to study how sugars and protein glycosylation mediate cell-cell communication.

抽象的细胞应力反应途径的正确激活使细胞可以适应和维持体内平衡在压力条件下。尽管通常认为这些途径在细胞内受到调节，但最近小鼠和秀丽隐杆线虫的研究表明，某些细胞中的细胞应激经历可以远端激活应激在其他组织中的反应。例如，我们实验室的工作表明神经元激活内质网展开的蛋白质反应（UPRER）在秀丽隐杆线虫的肠道中诱导了上祖，促进压力抗性和寿命。这些发现清楚地表明了系统性的重要性在生物健康中调节ER蛋白抑制剂。但是，机理和信号分子基本的此类组织间调节ER蛋白质的调节尚不清楚。我们的初步工作已经鉴定出N-乙酰葡萄糖（GlcNAC），这是蛋白质必不可少的代谢物糖基化，作为用于调节细胞ER蛋白毒素的候选信号分子。我建议阐明由应力细胞释放GlcNAC并被接受者细胞使用的机制，开发新的方法来检查使用神经元细胞培养和C. 秀丽隐杆线模型。这项工作将发现GlcNAC如何调节全身性ER蛋白质症，并建立新颖研究糖和蛋白质糖基化如何介导细胞 - 细胞通信的技术。