Partial Antagonists of IRE1 RNaseââPAIRâsâto treat Type 1 Diabetes

项目摘要/摘要 1型糖尿病(T1D)是一种以进行性高血糖为特征的慢性自身免疫性疾病 免疫介导的对胰岛β细胞的破坏。我们实验室最近的研究表明 免疫靶向的β细胞对内质网应激的未折叠蛋白反应(UPR)的过度激活可能是 这是T1D发育过程中的一个关键早期事件。我们开发了一种新的药理试剂，名为 ‘PAIR允许我们操纵普遍定期审议的组成部分。重要的是，第一代版本的小型 被称为kiras的分子传递给NOD小鼠可以有效地预防甚至逆转糖尿病 T1D模型。因此，在这笔合作赠款中，我们将利用 研究人员优化这对先导分子的效力和选择性，进行概念验证 利用人类胰岛进行研究，并执行必要的关键使能步骤，以使这些候选人进一步进入 治疗人类T1D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.