Cytoprotection of Beta Cells Through Modulation of Ire1Alpha Function

通过调节 Ire1Alpha 功能对 Beta 细胞进行细胞保护

基本信息

批准号：
9065686
负责人：
Feroz R Papa
金额：
$ 33.29万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2009-07-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9065686
关键词：
Affect American Apoptosis Apoptotic Attenuated Beta Cell Cell Death Cell Fate Control Cell Survival Cell physiology Cells Cessation of life Collection Cytoprotection Degenerative Disorder Development Diabetes Mellitus Disease Disease Progression Endoplasmic Reticulum Endoribonucleases Eukaryota Event Feedback Functional disorder Genes Glucose Goals Growth Health Healthcare Homeostasis Human Inbred NOD Mice Individual Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Integral Membrane Protein Islet Cell Islets of Langerhans Knowledge Learning Link Measures Mediating Mediator of activation protein Membrane Messenger RNA MicroRNAs Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nucleotides Orthologous Gene Outcome Output Pathway interactions Peripheral Phosphotransferases Physiological Process Productivity Proteins RNA RNA Splicing Research Resolution Ribonucleases Risk Saccharomyces cerevisiae Second Messenger Systems Signal Pathway Signal Transduction Signaling Protein Site Somatic Mutation Stress System Testing Translations Work assault base cost endoplasmic reticulum stress feeding inhibitor/antagonist insight insulin secretion islet kinase inhibitor monomer novel prevent programs protein folding response second messenger secretory protein small molecule therapy development tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Numerous recent studies link development of diabetes to endoplasmic reticulum (ER) stress, a condition that occurs whenever protein-folding requirements overwhelm protein-folding capacity in the secretory pathway. Notably, there is mounting evidence that ER stress contributes to diminished glucose-responsive insulin secretion in �-cells, to �-cell apoptosis, and to general peripheral insulin resistance, all hallmarks of type 2 diabetes; additionally ER stress is evident in type 1 diabetes. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionally upregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that key components of the UPR, act as toggling switches between homeostatic and apoptotic outputs, ultimately controlling �-cell fate. Our project goal is to study these switches at the molecular level, using interventional approaches.

描述（由申请人提供）：最近的许多研究将糖尿病的发展与内质网（ER）应激联系起来，当蛋白质折叠需求超过分泌途径中的蛋白质折叠能力时就会发生这种情况。值得注意的是，越来越多的证据表明内质网应激。导致 β 细胞中葡萄糖反应性胰岛素分泌减少、β 细胞凋亡和一般外周胰岛素抵抗，这些都是 2 型糖尿病的特征；内质网应激在 1 型糖尿病中很明显，内质网应激会触发未折叠蛋白反应 (UPR) 途径，该途径会减慢翻译速度并上调增强内质网蛋白折叠能力的基因，如果这些输出不能恢复体内平衡，UPR 就会引发细胞凋亡。我们一直在寻找 UPR 的关键组成部分，作为稳态和凋亡输出之间的切换开关，最终控制细胞的命运。我们的项目目标是在分子水平上研究这些开关。使用介入方法。