Partial Antagonists of IRE1 RNaseââPAIRâsâto treat Type 1 Diabetes

项目总结/摘要 1型糖尿病（T1 D）是一种慢性自身免疫性疾病，其特征在于由于进行性糖尿病引起的高血糖症。 免疫介导的胰腺β细胞破坏。我们实验室最近的工作表明， 免疫靶向的β细胞中对ER应激的未折叠蛋白应答（UPR）的超活化可能是 这是T1 D发展的关键早期事件。我们开发了一种新的药理学试剂， `PAIR使我们能够操纵普遍定期审议的组成部分。重要的是，第一代小型 分子-称为KIRA-交付给NOD小鼠可以有效地预防，甚至逆转糖尿病， T1 D模型。因此，在这项合作赠款中，我们将利用 研究人员优化这些PAIR先导分子的效力和选择性，进行概念验证 研究使用人类胰岛，并执行关键的使能步骤，需要进一步推进这些候选人， 治疗T1 D患者的诊所

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by hyperglycemia due to progressive immune-mediated destruction of pancreatic beta cells. Recent work from our laboratories has shown that hyperactivation of the unfolded protein response (UPR) to ER stress in the immune-targeted beta cells may be a critical early event in the development of T1D. We have developed novel pharmacological reagents called `PAIR's that allow us to manipulate components of the UPR. Importantly, first generation versions of small molecules—called KIRAs— delivered to NOD mice can efficaciously prevent and even reverse diabetes in this T1D model. Thus, in this collaborative grant we will capitalize on the complementary expertise of the investigators to optimize these PAIR lead molecules for potency and selectivity, conduct proof of concept studies using human islets, and perform key enabling steps needed to advance these candidates further into the clinic for treating human patients with T1D.