Role of the Unfolded Protein Response in Beta Cell

未折叠蛋白反应在 Beta 细胞中的作用

基本信息

批准号：
7996351
负责人：
RANDAL J. KAUFMAN
金额：
$ 27.11万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-20 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7996351
关键词：
Attenuated Beta Cell Blood Glucose Cell Death Cell physiology Cells Diabetes Mellitus Disease Endoplasmic Reticulum Environment Eukaryotic Initiation Factors Failure Financial compensation Functional disorder Genes Genetic Glucose Grant Insulin Insulin Resistance Intervention Laboratories Lead Mediating Modality Molecular Morbidity - disease rate Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Pancreas Pathway interactions Phosphorylation Production Progress Reports Proinsulin Prokaryotic Initiation Factor-2 Protein Biosynthesis Proteins Publishing Role Signal Pathway Signal Transduction Signal Transduction Pathway Testing Therapeutic Therapeutic Intervention Tissues base human disease improved in vivo Model insight insulin secretion meetings mortality mouse model novel prevent protein folding response sensor stem transcription factor CHOP

项目摘要

DESCRIPTION (provided by applicant): Diabetes is a world-wide major cause of morbidity and mortality that is associated with disturbances in ¿ cell function that result in the loss of glucose-stimulated insulin secretion for control of blood glucose. Recent studies demonstrated an association between ¿ cell function and/or survival with an intracellular signaling pathway termed the unfolded protein response (UPR). Upon accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER), three UPR signal transduction subpathways are activated to increase the protein folding capacity and increase the protein degradative machinery. Protein synthesis is transiently attenuated through PERK-mediated phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (elF2a), one subpathway of the UPR. Recently, we discovered that PERK/elFa signaling is required to preserve the environment of the ER to support high-level insulin production in response to increases in blood glucose. Our discoveries support the hypothesis that increases in insulin production exceed the protein-folding capacity of the ER. Under these conditions, the PERK/elF2a subpathway is activated transiently to prevent oxidative stress, and when perpetually activated, induces a cell death response through induction of the transcription factor CHOP. We propose that reducing oxidative stress or preventing CHOP expression will improve ¿ cell function and survival in response to insulin resistance. Given the significance of the PERK/elF2a UPR subpathway in ¿ cell function, is it likely that IRE1 and ATF6 UPR subpathways are also essential for ¿ cell function. The studies proposed will elucidate the requirements of PERK/elF2a, IRE1, and ATF6 signaling using novel genetic mouse models in which UPR sensor genes can be turned 'on' or 'off' in a temporal- and/or tissue-specific manner. These in vivo models will be used to elucidate novel insights into ¿ cell failure and to evaluate novel modalities for therapeutic intervention. Diabetes is a multifactorial disease that stems largely from an inability of pancreatic ¿ cells to produce adequate amounts of insulin for control of blood glucose levels. Excessive insulin synthesis can lead to accumulation of unfolded protein within the ¿ cell. The study of cell signaling pathways activated by unfolded protein will lead to insights and new treatments for this disease.

描述（由应用提供）：糖尿病是与细胞功能灾害有关的全球发病率和死亡率的主要原因，导致葡萄糖刺激的胰岛素分泌失去控制血糖。最近的研究表明，细胞功能与/或存活与细胞内信号传导途径之间存在关联，称为展开的蛋白质反应（UPR）。在内质网（ER）的腔内积累中展开的蛋白质后，激活了三个UPR信号转移子路口以增加蛋白质折叠能力并增加蛋白质降解机械。蛋白质合成通过真核翻译起始因子2（ELF2A）的Alpha亚基的PERK介导的磷酸化（ELF2A）瞬时减弱。最近，我们发现需要PERK/ELFA信号传导来保护ER的环境以支持高级胰岛素的产生，以响应增加血糖的增加。我们的发现支持以下假设，即胰岛素产生的增加超过了ER的蛋白质折叠能力。在这些条件下，PERK/ELF2A子路口会瞬时激活以防止氧化应激，并且在永久激活时，通过诱导转录因子CHOP诱导细胞死亡反应。我们提出，减少氧化应激或预防CHOP表达将改善细胞功能和对胰岛素抵抗的响应。鉴于PERK/ELF2A UPR子路口在细胞功能中的重要性，IRE1和ATF6 UPR子路径很可能对于细胞功能也是必不可少的。提出的研究将使用新型的遗传小鼠模型来阐明PERK/ELF2A，IRE1和ATF6信号的需求，其中可以以临时和/或组织特异性方式将UPR传感器基因“ ON”或“ OFF”打开。这些体内模型将用于阐明对细胞衰竭的新见解，并评估新型的治疗干预方式。糖尿病是一种多因素疾病，主要来自胰腺细胞无法产生足够量的胰岛素来控制血糖水平的足够含量。过度的胰岛素合成可以导致渗透蛋白在细胞内的积累。对未折叠蛋白激活的细胞信号通路的研究将导致对该疾病的见解和新治疗方法。