Cytoprotection of Beta Cells Through Modulation of Ire1Alpha Function

描述(申请人提供)：许多最近的研究将糖尿病的发展与内质网(ER)压力联系在一起，内质网(ER)压力是一种当蛋白质折叠需求超过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，内质网应激导致�细胞葡萄糖反应性胰岛素分泌减少，�细胞凋亡，以及全身外周胰岛素抵抗，这些都是2型糖尿病的特征；此外，内质网应激在1型糖尿病中很明显。内质网应激触发未折叠蛋白反应(UPR)途径，这会减缓翻译速度，并在转录上上调增强内质网蛋白折叠能力的基因。如果动态平衡没有通过这些输出恢复，UPR反而会触发细胞凋亡。我们假设，UPR的关键成分在稳态和凋亡输出之间起到切换开关的作用，最终控制�细胞的命运。我们的项目目标是使用干预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.