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Proinsulin ER Export and Beta Cell ER Homeostasis in Health and Diabetes

健康和糖尿病中的胰岛素原 ER 输出和 β 细胞 ER 稳态

基本信息

批准号：
9767125
负责人：
Xuequn Chen
金额：
$ 34.66万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767125
关键词：
Address Affect Animal Model Apoptosis Beta Cell Biochemical Biogenesis Biological Assay Capsid Proteins Cell Death Cell Line Cell Survival Cell physiology Cessation of life Chronic Coated vesicle Coupled Defect Development Diabetes Mellitus Diabetic mouse Endoplasmic Reticulum Environment Enzymes Equilibrium Failure Functional disorder Gene Expression Genes Genetic Glucose Golgi Apparatus Health Homeostasis Human Image Analysis Impairment In Vitro Individual Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Knowledge Lipids Membrane Molecular Molecular Chaperones Monitor Non-Insulin-Dependent Diabetes Mellitus Organelles Pathogenesis Pathway Analysis Pathway interactions Physiological Play Positioning Attribute Process Production Proinsulin Protein Biosynthesis Protein Export Pathway Proteins Proteomics Rodent Role Structure of beta Cell of islet Systems Biology Techniques Testing Time Toxic effect United States Vesicle Western Blotting diabetic diabetogenic endoplasmic reticulum stress genome wide association study heat-shock proteins 40 imaging approach immunocytochemistry improved innovation islet novel novel therapeutics protein complex protein folding proteostasis public health relevance quantitative imaging

项目摘要

PROJECT SUMMARY Up to date, most of the diabetes-associated genes identified in genome-wide association studies are enriched in the pancreatic beta cells. Beta cell failure plays a central role in the development and progression of type 2 diabetes (T2D). The endoplasmic reticulum (ER) is a central organelle for the massive production and processing of proinsulin. ER homeostasis is critical for normal beta cell function and is maintained by the delicate balance between protein synthesis, folding, export and degradation. In contrast, the disruption of ER homeostasis, by many genetic and environmental diabetes-causing factors, induces ER stress and causes beta cell death in T2D. Compared to our knowledge in protein synthesis, folding and degradation in beta cell ER, the role of ER export in proinsulin biogenesis and ER homeostasis is much less understood. This proposal addresses this knowledge gap. We have obtained strong preliminary results demonstrating that ER exit of proinsulin requires COPII (coat protein complex II) coated vesicles and defective COPII dependent ER export strongly induces ER stress. In addition to our results, evidence has recently begun to emerge that reduced ER-Golgi transport is causative to lipotoxicity-induced ER stress in beta cells. On the basis of these novel findings, we aim to determine how glucose- and lipid-toxicity affect the ER export of protein cargo, particularly proinsulin, in beta cells and how defective ER export, in turn, contributes to ER stress and beta cell dysfunction. Over a thousand proteins, referred to as the proteostasis network, have been proposed to maintain ER homeostasis. However, to date, only a very small number of ER proteins have been investigated for their involvement in ER stress or proinsulin biogenesis in beta cells. A systematic proteomics analysis is needed to comprehensively understand how different diabetes-causing conditions perturb beta cell ER homeostasis at the onset of T2D. In this proposal, using systems biology approaches, we will test the central hypothesis that diabetogenic factors such as glucolipotoxicity disrupt beta cell ER function through perturbing ER protein homeostasis and COPII dependent ER export. There are two specific aims in this proposal: 1) Determine how COPII dependent ER export is regulated in health and diabetes; 2) Determine how ER chaperones and folding enzymes are altered in diabetes and how these changes affect beta cell ER export. This study will use state-of-the-art quantitative proteomics and other systems biology approaches to characterize the molecular mechanisms by which diabetes-causing conditions differentially alter ER homeostasis. The emphasis will be on the ER export, an under-investigated component of beta cell ER homeostasis.

项目总结