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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：
8695105
负责人：
Feroz R Papa
金额：
$ 33.16万
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/8695105
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 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 endoribonuclease feeding inhibitor/antagonist insight insulin secretion islet kinase inhibitor monomer novel prevent programs protein folding public health relevance 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）：许多最近的研究将糖尿病的发展与内质网（ER）应激联系起来，内质网应激是一种在分泌途径中蛋白质折叠需求压倒蛋白质折叠能力时发生的病症。值得注意的是，有越来越多的证据表明，ER应激有助于减少葡萄糖反应性胰岛素分泌的细胞，细胞凋亡，和一般的外周胰岛素抵抗，所有的2型糖尿病的标志;此外，ER应激是明显的1型糖尿病。ER应激触发未折叠蛋白反应（UPR）途径，其减慢翻译并转录上调增强ER蛋白折叠能力的基因。如果体内平衡没有通过这些输出恢复，UPR反而触发细胞凋亡。我们假设UPR的关键成分在稳态和凋亡输出之间起着切换开关的作用，最终控制着细胞的命运。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。