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Caraballo Diversity Supplement 093019

Caraballo 多样性补充剂 093019

基本信息

批准号：
10026554
负责人：
Feroz R Papa
金额：
$ 11.39万
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：
2019-02-01 至 2020-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10026554
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 Epithelium Etiology Event Excision Extracellular Matrix Extracellular Matrix Proteins Feedback Fibroblasts Fibrosis Functional disorder Future Genetic Heat-Shock Proteins 90 Homeostasis Homo Human Hyperactive behavior 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 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.

项目总结/摘要在这个MPI RO 1的应用中，我们发现高内质网（ER）应激和失调的未折叠的在肺纤维化小鼠模型中，肺中的蛋白质应答（UPR）信号传导先于纤维化的发展。在患有特发性肺纤维化（PF）的人类患者的肺中已经报道了类似的变化。纤维化（IPF）。我们发现，这些变化的特征是由于过度活跃的信号， IRE 1 α，一种含有双功能激酶/核糖核酸内切酶（RNase）催化的ER跨膜蛋白活动我们已经发现，新型的IRE 1 α的小分子UPR激酶抑制剂，称为KIRA（一个缩写），激酶抑制RNA酶衰减剂）减少IRE 1 α的破坏性UPR信号传导，并显示出有效的抗在ER应激的小鼠肺中的纤维化作用。因此，即使IRE 1 α成为一个潜在的治疗靶点，治疗患有IPF的人类患者，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介导的对减少肺上皮损伤、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的胶原过度产生。该项目由两个实验室（Papa和Sheppard）的互补技能组合，共同发现UPR是通过导致肺中经典TGF-β诱导的促纤维化信号传导的信号传导环。因此，从成功完成拟议的研究中获得的理解有望揭示新的目前无法治愈的特发性肺纤维化，疾病