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

肺纤维化中 IRE1α-TGFβ 信号环路的介入靶向治疗

基本信息

批准号：
10318632
负责人：
Feroz R Papa
金额：
$ 69.77万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318632
关键词：
Aerosols Apoptosis Bleomycin Cell Death Cell Differentiation process Cells Cessation of life Clinical Research Collagen Complex Development Disease Dose Endoplasmic Reticulum Endoribonucleases Epithelial Epithelial Cells Etiology Event Excision Extracellular Matrix Extracellular Matrix Proteins Feedback Fibroblasts Fibrosis Functional disorder Future Genetic Heat-Shock Proteins 90 Homeostasis Homo Human Hyperactivity Injury Integral Membrane Protein Integrins Intervention Lead Learning Limb structure Link Lung Mediating Membrane Messenger RNA MicroRNAs Modeling Modification Molecular Chaperones Mus Oral Outcome Output Pathogenesis Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenocopy Phosphorylation Phosphotransferases Play Production Profibrotic signal Protein Secretion Proteins Pulmonary Fibrosis Pulmonary Surfactants RNA Splicing Receptor Serine/Threonine Kinase Regulation Reporting Resolution Ribonucleases Role Secretory Cell Signal Pathway Signal Transduction System TGF Beta Signaling Pathway Testing Transforming Growth Factor beta Transforming Growth Factor beta Receptors Up-Regulation Work XBP1 gene acronyms alveolar epithelium attenuation base biological adaptation to stress cell injury dimer endoplasmic reticulum stress epithelial injury experience idiopathic pulmonary fibrosis in vivo insight kinase inhibitor mouse model nanomolar novel novel drug class novel therapeutics prevent response senescence skills small molecule therapeutic target tool transcription factor transdifferentiation

项目摘要

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.

项目概要/摘要在此 MPI RO1 应用中，我们展示了高内质网 (ER) 应激和失调在小鼠肺纤维化模型中，肺部的蛋白质反应（UPR）信号先于纤维化的发展纤维化（PF）——特发性肺纤维化患者的肺部也有类似的变化纤维化（IPF）。我们发现这些变化的病理特征是由于过度活跃的信号传导所致 IRE1α，一种内质网跨膜蛋白，含有双功能激酶/核糖核酸内切酶 (RNase) 催化作用活动。我们发现了 IRE1α 的新型小分子 UPR 激酶抑制剂，称为 KIRA（缩写用于激酶抑制 RNase 衰减剂）减少 IRE1α 的破坏性 UPR 信号传导并显示出有效的抗- 内质网应激小鼠肺部的纤维化效应。因此，即使 IRE1α 成为潜在的治疗靶点，治疗患有 IPF 的人类患者，这是细胞保护、抗纤维化、需要了解 KIRA 化合物的功效。通过这个应用程序，我们建议了解 KIRA 介导的减少肺上皮损伤、失调和死亡的有益作用的基础，以及减少活化的成纤维细胞过度产生胶原蛋白。该项目是由两个实验室（Papa 和 Sheppard）的互补技能组合共同发现 UPR 是通过有线连接的导致肺部经典 TGF-β 诱导的促纤维化信号传导的信号传导环路。因此，机械从成功完成拟议研究中获得的理解有望揭示新的特发性肺纤维化（目前无法治愈）的合理疾病调整的节点和目标疾病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung.

IRE1α 激酶/RNase 的小分子抑制具有抗肺纤维化作用。

DOI：
10.1371/journal.pone.0209824
发表时间：
2019
期刊：
PloS one
影响因子：
3.7
作者：
Thamsen,Maike;Ghosh,Rajarshi;Auyeung,VincentC;Brumwell,Alexis;Chapman,HaroldA;Backes,BradleyJ;Perara,Gayani;Maly,DustinJ;Sheppard,Dean;Papa,FerozR
通讯作者：
Papa,FerozR