Cytoprotection of Beta Cells Through Modulation of Ire1Alpha Function

描述（由申请人提供）：许多最近的研究将2型糖尿病（T2 D）的发展与内质网（ER）应激联系起来，内质网应激是一种在分泌途径中蛋白质折叠需求压倒蛋白质折叠能力时发生的疾病。值得注意的是，有越来越多的证据表明，ER应激有助于减少葡萄糖反应性胰岛素分泌？细胞，到？细胞凋亡和一般外周胰岛素抵抗，所有T2 D的标志。ER应激触发未折叠蛋白反应（UPR）途径，其减慢翻译并转录上调增强ER蛋白折叠能力的基因。如果体内平衡没有通过这些输出恢复，UPR反而触发细胞凋亡。我们假设UPR的关键组成部分，作为一个平衡和凋亡输出之间的切换开关，最终控制？细胞命运我们的项目目标是使用介入方法在分子水平上研究这些开关。公共卫生相关性：2型糖尿病（T2 D）影响着1800万美国人，每年的国家医疗保健和生产力损失超过1000亿美元。2型糖尿病开始作为一个国家的补偿胰岛素抵抗;弗兰克疾病发展时，约50%的胰岛素产生胰岛？受影响个体的细胞经历细胞死亡。详细了解2-细胞如何死亡对于合理地攻击T2 D是必要的。我们推测过度工作的压力可能是？- T2 D中的细胞死亡。在本提案中，我们正在使用分子和细胞方法测试这一概念。

DESCRIPTION (provided by applicant): Numerous recent studies link development of type 2 diabetes (T2D) 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 T2D. 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 component of the UPR, act as a 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. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus (T2D) affects 18 million Americans, with national healthcare and lost productivity costs exceeding $100 billion per year. T2D begins as a state of compensated insulin resistance; frank disease develops when approximately 50% of insulin-producing pancreatic islet ?-cells of affected individuals undergo cell death. A detailed understanding of how 2-cells die is necessary to rationally mount an assault on T2D. We hypothesize that the stress from having to overwork may be responsible for ?-cell death in T2D. In this proposal we are testing this concept using molecular and cellular approaches.