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(T2D)的发生与内质网(ER)应激联系在一起，内质网(ER)应激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β细胞葡萄糖反应性胰岛素分泌减少，导致β细胞凋亡，并导致全身外周胰岛素抵抗，这些都是T2D的特征。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，作为在稳态和凋亡输出之间切换的开关，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。公共卫生相关性：2型糖尿病(T2D)影响着1800万美国人，每年全国医疗保健和生产力损失超过1000亿美元。T2D始于一种代偿性胰岛素抵抗状态；当受影响个体中大约50%的产生胰岛素的胰岛细胞经历细胞死亡时，弗兰克病就会发展。对2-细胞如何死亡的详细了解对于理性地对T2D发动攻击是必要的。我们推测，过度工作带来的压力可能是T2D中细胞死亡的原因。在这项提案中，我们正在使用分子和细胞方法来测试这一概念。

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.