Interventional Targeting of the IRE1alpha-TGFbeta signaling loop in pulmonary fibrosis

项目摘要/摘要 在这个MPI RO1的应用中，我们展示了高内质网(ER)应激和失调的展开 肺组织蛋白反应(UPR)信号转导先于肺纤维化的发生 纤维化(PF)--人类特发性肺病患者的肺部也有类似的改变。 纤维化(IPF)。我们发现，这些变化的病原学特征是由于过度活跃的信号通过 内质网跨膜蛋白IRE1α，含双功能激酶/核糖核酸酶催化 活动。我们发现了一种新的、小分子的IRE1α的UPR激酶抑制剂，称为KIRAS(缩写 对于激酶抑制核糖核酸酶衰减剂)减少IRE1α‘S破坏性的UPR信号，并显示出强大的抗 内质网应激对小鼠肺纤维化的影响。因此，即使IRE1α成为潜在的治疗靶点 治疗人类IPF患者，其潜在的机制基础是细胞保护、抗纤维化、 需要了解Kira化合物的功效。通过此应用程序，我们建议了解 KIRA介导的有益作用在减少肺上皮损伤、调节失调和死亡方面的基础 以及通过激活的成纤维细胞减少胶原蛋白的过度产生。该项目由 两个实验室(爸爸和谢泼德)的互补技能组合，他们共同发现普遍定期审议是通过 一个信号环，导致典型的转化生长因子-β诱导的肺内促纤维化信号。因此，机械论 从成功完成拟议研究中获得的谅解有望揭示新的 特发性肺纤维化的合理疾病修改的节点和目标，目前无法治愈 疾病。

PROJECT SUMMARY/ABSTRACT In this MPI RO1 application, we show that high endoplasmic reticulum (ER) stress and dysregulated unfolded protein response (UPR) signaling in lungs precedes development of fibrosis in murine models of pulmonary fibrosis (PF)—similar changes have been reported in lungs of human patients with idiopathic pulmonary fibrosis (IPF). We find that the pathognomonic features of these changes are due to hyperactive signaling by IRE1α, an ER transmembrane protein containing bifunctional kinase/endoribonuclease (RNase) catalytic activities. We have found that novel, small molecule UPR kinase inhibitors of IRE1α, called KIRAs (an acronym for kinase-inhibiting RNase attenuators) reduce IRE1α's destructive UPR signaling and show potent anti- fibrotic effects in ER-stressed lungs of mice. Thus, even as IRE1α emerges as a potential therapeutic target for treating human patients suffering from IPF, the underlying mechanistic basis for the cytoprotective, anti-fibrotic, efficacy of the KIRA compounds needs to be understood. Through this application, we propose to understand the basis of the KIRA-mediated salutary effects on reducing lung epithelial injury, dysregulation, and death, and also on reducing collagen overproduction by activated fibroblasts. The project is enabled by the complementary skill sets of two labs (Papa and Sheppard) that together have found the UPR is wired through a signaling loop that leads to classical TGF-β-induced, pro-fibrotic signaling in lungs. Thus, the mechanistic understanding to be gained from the successful completion of the proposed studies promises to reveal new nodes and targets for rational disease modification in idiopathic pulmonary fibrosis, a currently incurable disease.