权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pre-Clinical Evaluation of IRE1beta as a Novel Therapeutic Target for Cystic Fibrosis Airway Mucus Production

IRE1beta 作为囊性纤维化气道粘液产生的新治疗靶点的临床前评估

基本信息

批准号：
10296058
负责人：
Carla Maria Pedrosa Ribeiro
金额：
$ 46.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10296058
关键词：
Address Affect Airway Disease Amino Acids Anti-Inflammatory Agents Asthma Attenuated Bacterial Infections Binding Binding Proteins Birth Bronchiectasis Bronchiolitis Cells Child Chronic Clinic Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Cytoplasmic Tail Data Distal Endoplasmic Reticulum Enzymes Epithelial Exhibits Feedback Gastrointestinal tract structure Generations Genetic Human Impairment Inflammation Inositol Integral Membrane Protein Interleukin-1 Lead MAPK8 gene MUC5AC gene MUC5B gene Mammals Mediating Medical Messenger RNA Modeling Mucins Mucous body substance Mus Obstruction Para-Influenza Virus Type 1 Pathway interactions Pharmacology Phosphotransferases Preclinical Testing Production Protein Isoforms Proteins Pulmonary Cystic Fibrosis Pulmonary Fibrosis RNA Splicing Regulation Respiratory Syncytial Virus Infections Respiratory System Respiratory syncytial virus Ribonucleases Role Signal Pathway Structure TNF gene Tertiary Protein Structure Testing Therapeutic Effect VX-770 Viral Bronchiolitis Virulence Factors Virus Diseases airway epithelium airway inflammation bronchial epithelium cystic fibrosis airway cystic fibrosis airway epithelia cystic fibrosis mouse cystic fibrosis patients cytokine efficacy testing endoplasmic reticulum stress idiopathic pulmonary fibrosis infant infection inhibitor/antagonist innovation mutant neutrophil new therapeutic target novel therapeutics overexpression p38 Mitogen Activated Protein Kinase preclinical evaluation prevent respiratory infection virus response sensor targeted treatment transcription factor

项目摘要

Cystic fibrosis (CF) lungs exhibit mucoinflammatory responses soon after birth, likely triggered by viral infections and/or aspiration. Respiratory syncytial virus (RSV) causes bronchiolitis leading to airway muco- obstruction in young CF children, who exhibit increases in MUC5B and MUC5AC mucins in their airways. Because no treatments are available for CF airway mucus overproduction, there is a clear unmet medical need for therapies that target mucin synthesis in CF airways. CF airway epithelial inflammation triggers endoplasmic reticulum (ER) stress and activates the inositol requiring enzyme 1 (IRE1), which exists in two isoforms, α and β. IRE1α is ubiquitous, but IRE1β is only expressed in mucous cells of the respiratory and GI tracts. We have shown that IRE1β (but not IRE1α) is required for airway mucin production. IRE1 is an ER transmembrane protein with a lumenal domain (sensor of unfolded proteins) and a cytoplasmic domain (effector) with kinase and RNase activities. It is unknown whether the IRE1 lumenal domain senses unfolded mucins and whether its cytoplasmic domains mediate mucin production; however, our previous studies suggested that mucin production triggers ER stress and activates IRE1β kinase-induced RNase activation. Because the activated IRE1 RNase splices the mRNA of X-box binding protein-1 (XBP-1s), a transcription factor that up-regulates mucin production, this may provide a mechanism for CF airway epithelial mucin overproduction. In non-mucous cells, IRE1 kinase activates JNK, p38 MAP kinase and NF-B via protein interactions, but it is unknown whether the IRE1 kinase activates these pathways, which are relevant to CF airways because they can promote mucin production. Our preliminary data indicate that IRE1β, MUC5AC and MUC5B levels are up-regulated in native CF human airways and in freshly isolated CF human distal airway epithelia. Over-expression of wild type IRE1 in primary human bronchial epithelia (HBE) increased mucin production, whereas over-expression of IRE1 mutants that lack kinase and/or RNase activities decreased mucin production. IL-1 and TNF, predominant CF airway cytokines, differently affected XBP-1s (only IL-1 increased XBP-1s) and mucin production (IL-1 > TNF) in HBE, suggesting that they up-regulate mucin production via IRE1β RNase-dependent and independent mechanisms. KIRA6, an IRE1 kinase + RNase inhibitor, blunted IL-1-increased XBP-1s and mucins in CF HBE. Notably, a combination of CFTR modulators (VX-445, VX-661 and VX-770) had no effect on mucin production. RSV infection of HBE increased XBP-1s and mucin production/secretion, and these responses were blunted by KIRA6. Finally, murine parainfluenza virus type 1-infected mice developed viral bronchiolitis and airway muco-obstruction, modeling the bronchiolitis in CF infants infected by RSV. Our aims will test the role of IRE1β protein domains in CF airway cytokine-increased mucin production in CF HBE. We will also evaluate the therapeutic effect of IRE1β inhibition on respiratory virus infection-induced mucin production in CF HBE and murine airways, including a CF mouse. Our studies may lead to the generation of IRE1β inhibitors as novel therapeutics for CF airway muco-obstruction.

囊性纤维化（CF）肺在出生后不久就表现出粘膜炎症反应，可能是由病毒引发的