Cytoprotection of Beta Cells Through Modulation of Ire1Alpha Function

描述（由申请人提供）：最近的许多研究将糖尿病的发展与内质网（ER）应激联系起来，内质网应激是一种蛋白质折叠需求压倒分泌途径中蛋白质折叠能力时发生的情况。值得注意的是，越来越多的证据表明，内质网应激有助于减少细胞中葡萄糖反应性胰岛素分泌、细胞凋亡和一般外周胰岛素抵抗，这些都是2型糖尿病的特征；此外，内质网应激在1型糖尿病中也很明显。内质网应激触发未折叠蛋白反应（UPR）途径，该途径减缓翻译并在转录上上调增强内质网蛋白折叠能力的基因。如果不能通过这些输出恢复体内平衡，UPR就会触发细胞凋亡。我们假设UPR的关键成分在稳态和凋亡输出之间充当切换开关，最终控制细胞的命运。我们的项目目标是使用介入性方法在分子水平上研究这些开关。

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.