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

描述（由申请方提供）：分泌途径的客户蛋白通过分子伴侣、氧化还原酶和其他蛋白质修饰酶催化的反应折叠至内质网（ER）中的天然结构。然而，在高分泌需求下，这些ER驻留活动变得不堪重负，导致客户蛋白以未折叠形式在ER内积累。这种情况称为内质网应激，使受影响的细胞死亡的风险增加。因此，未经检查的ER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。ER中的未折叠蛋白触发称为未折叠蛋白反应（UPR）的信号传导途径。在可补救的ER应激水平下，UPR启动促进适应的转录和翻译变化。但是，当面对无法补救的ER应激水平时，这些适应性措施失败，UPR转而切换策略以触发程序性细胞死亡-我们将这种结果称为终端UPR。我们的总体目标是这个R 01是双重的：（1）阐明潜在的分子机制，通过终端UPR和氧化应激协同作用，导致胰腺？细胞变性，和（2）治疗性靶向终末UPR中的关键节点以保护免受糖尿病小鼠模型的影响。阐明连接ER和氧化应激信号传导组分的机制有望开发治疗包括糖尿病在内的多种细胞退行性疾病的新药。

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.