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

描述（由申请人提供）：分泌途径的客户蛋白通过伴侣、氧化还原酶和其他蛋白质修饰酶催化的反应折叠到内质网（ER）中的天然结构。然而，在高分泌需求下，这些内质网活性变得不堪重负，导致客户蛋白在内质网内以未折叠的形式积累。这种情况被称为内质网应激，会增加受影响细胞的死亡风险。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发展的核心，包括神经变性和2型糖尿病。内质网中的未折叠蛋白触发称为未折叠蛋白反应（UPR）的信号通路。在可补救的内质网应激水平下，普遍定期审议启动促进适应的转录和翻译变化。但当面临无法补救的内质网应激水平时，这些适应性措施失效，UPR转而切换策略触发程序性细胞死亡-我们将这种结果称为终端UPR。我们对这个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导致胰腺细胞凋亡的潜在分子机制。(2)治疗性地靶向终末UPR中的关键节点，以防止小鼠糖尿病模型。对内质网和氧化应激信号组分之间的机制的阐明，有望开发出治疗多种细胞退行性疾病（包括糖尿病）的新药。

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.