Attenuating ER and oxidative stress signaling to reduce cell degeneration in vivo

减弱 ER 和氧化应激信号以减少体内细胞变性

• 批准号: 8505075
• 负责人: Scott A. Oakes
• 金额: $ 38.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505075
• 关键词: Affect; Apoptosis; Apoptotic; Attenuated; Blood Glucose; Cell Death; Cell Fate Control; Cells; Cessation of life; Client; Data; Degenerative Disorder; Development; Diabetes Mellitus; Diabetic mouse; Endoplasmic Reticulum; Endoribonucleases; Enzymes; Genetic; Goals; Human; Inflammation Mediators; Inflammatory; Insulin; Interleukins; Lead; Life; Link; Measures; Modeling; Molecular; Molecular Chaperones; Motion; Mus; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Output; Oxidative Stress; Oxidoreductase; Pancreas; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Physiological; Proinsulin; Proteins; Reaction; Reactive Oxygen Species; Research Project Grants; Ribonucleases; Risk; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Structure of beta Cell of islet; Suicide; Testing; Therapeutic; Thioredoxin; Variant; Work; base; blood glucose regulation; cell injury; chemical genetics; endoplasmic reticulum stress; endoribonuclease; human disease; in vivo; injured; insight; novel; novel strategies; programs; public health relevance; response; secretory protein; small molecule; tool

DESCRIPTION (provided by applicant): Client proteins of the secretory pathway fold to their native structures in the endoplasmic reticulum (ER) through reactions that are catalyzed by chaperones, oxidoreductases, and other protein-modifying enzymes. However, under high secretory demand these ER-resident activities become overwhelmed, leading client proteins to accumulate in unfolded forms within the ER. This condition-termed ER stress-puts affected cells at increased risk for death. As such, unchecked ER stress is now recognized as being central to the development of various human diseases of cell loss, including neurodegeneration and Type 2 diabetes. Unfolded proteins in the ER trigger signaling pathways called the unfolded protein response (UPR). Under remediable levels of ER stress, the UPR sets in motion transcriptional and translational changes that promote adaptation. But when confronted with irremediable levels of ER stress, these adaptive measures fail and the UPR instead switches strategies to trigger programmed cell death-we refer to this outcome as the terminal UPR. Our overall goal for this R01 is twofold: (1) elucidate underlying molecular mechanisms through which the terminal UPR and oxidative stress synergize to cause pancreatic ?-cell degeneration, and (2) therapeutically target key nodes in the terminal UPR to protect against mouse models of diabetes. The elucidation of mechanisms connecting ER and oxidative stress signaling components holds the promise of developing novel drugs to treat diverse cell degenerative diseases, including diabetes.

描述（由申请人提供）：分泌途径的客户蛋白通过由伴侣，氧化还原酶和其他蛋白质修饰酶催化的反应，将内质网（ER）中的天然结构折叠。但是，在高分泌的要求下，这些居民居民活动变得不知所措，导致客户蛋白在急诊室内以不折叠的形式积累。这种条件处理的ER压力会影响死亡风险增加的细胞。因此，现在被认为不受检查的ER应力是对各种人类细胞损失的发展（包括神经退行性和2型糖尿病）的核心。 ER触发信号通路中展开的蛋白质称为展开的蛋白质反应（UPR）。在可补充的ER应力水平下，UPR将运动转录和翻译变化设置为促进适应。但是，当面对不可恢复的ER应力水平时，这些适应性措施失败了，而UPR则切换策略以触发编程的细胞死亡，我们将此结果称为终端UPR。我们对R01的总体目标是双重的：（1）阐明终端UPR和氧化应激协同作用以引起胰腺变性的基本分子机制，以及（2）治疗上靶向终端UPR中的关键节点以保护糖尿病小鼠模型。阐明连接ER和氧化应激信号传导成分的机制有望开发新的药物来治疗包括糖尿病在内的各种细胞退行性疾病。