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: 8675849
• 负责人: Scott A. Oakes
• 金额: $ 38.33万
• 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/8675849
• 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在内质网（ER）中通过分子伴侣、氧化还原酶和其他蛋白质修饰酶催化的反应折叠成其天然结构。然而，在高分泌需求下，这些内质网驻留的活动变得不堪重负，导致客户蛋白在内质网内以未折叠形式积累。这种被称为内质网应激的情况会使受影响的细胞面临更高的死亡风险。因此，不受控制的内质网应激现在被认为是各种人类细胞损失疾病（包括神经变性和 2 型糖尿病）发展的核心。内质网中的未折叠蛋白会触发称为未折叠蛋白反应 (UPR) 的信号通路。在可修复的内质网应激水平下，UPR 启动转录和翻译变化，促进适应。但当面临无法挽回的内质网应激水平时，这些适应性措施就会失效，UPR 反而会切换策略来触发程序性细胞死亡——我们将这种结果称为终端 UPR。我们对此 R01 的总体目标有两个：(1) 阐明末端 UPR 和氧化应激协同作用导致胰腺 β 细胞变性的潜在分子机制，以及 (2) 治疗性靶向末端 UPR 中的关键节点以预防小鼠模型糖尿病。 ER 和氧化应激信号传导成分之间的连接机制的阐明有望开发出治疗多种细胞退行性疾病（包括糖尿病）的新药。