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Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling

FOXM1在慢性肺重塑中调控的分子机制

基本信息

批准号：
10407550
负责人：
Vladimir Kalinichenko
金额：
$ 55.93万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-03-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407550
关键词：
Ablation Acute Acute Lung Injury Allergens Alveolar Alveolar Macrophages Animals Antibodies Applications Grants CCL2 gene Cell Count Cell Differentiation process Cell physiology Cells Chronic Chronic Obstructive Pulmonary Disease Data Embryo Epidermal Growth Factor Receptor Epithelial Cells Evaluation Exposure to FOXM1 gene Flow Cytometry Genes Genetic Genetic Transcription Goblet Cells Histologic Histology House Dust Mite Allergens Human In Vitro Inflammation Inflammation Mediators Inflammatory Interleukin-13 Knockout Mice Lasers Lung MAP Kinase Gene MUC5AC gene Matrix Metalloproteinases Mechanics Metaplastic Cell Methylcholanthrene Modeling Molecular Molecular Target Mucinous Mucous body substance Mus Myeloid Cells Pathogenesis Pathway interactions Patients Peptide Hydrolases Pharmacology Production Proteins Pulmonary Emphysema Pulmonary Inflammation Rattus Respiratory physiology Role STAT3 gene Signal Pathway Smoking Testing Transgenes Transgenic Organisms Treatment Efficacy Type II Epithelial Receptor Cell Ubiquitination airway epithelium airway remodeling alveolar epithelium alveolar type II cell asthma model cell type chemokine chronic respiratory disease cigarette smoke efficacy evaluation experimental study exposure to cigarette smoke forkhead protein gain of function genetic approach high throughput screening improved in vivo influenza infection inhibitor loss of function lung carcinogenesis macrophage monocyte mouse genetics multicatalytic endopeptidase complex novel overexpression prevent recruit response small molecule therapeutic evaluation therapeutic target therapy outcome transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY. COPD is a severe chronic respiratory disease, which is associated with smoking and characterized by chronic lung inflammation, emphysema, airway remodeling and goblet cell metaplasia. Identification of new molecular targets is needed to improve therapeutic outcomes in COPD patients. Our grant application will explore the role of Forkhead transcription factor FOXM1 as a potential therapeutic target in mouse and rat COPD models. FOXM1 is an embryonic transcription factor, which is not expressed in quiescent lungs but aberrantly induced during lung carcinogenesis. We provide preliminary data demonstrating that FOXM1 is activated in airway epithelial cells, macrophages and type II cells of COPD patients and mice exposed to cigarette smoke (CS). Increased expression of FOXM1 in mouse and human lungs is associated with emphysema and goblet cell metaplasia. Transgenic overexpression of FOXM1 in alveolar type II cells exacerbated lung inflammation, leading to emphysema. Genetic deletion of Foxm1 gene from myeloid cells, including macrophages and monocytes, decreased pulmonary inflammation after acute lung injury. Genetic ablation of Foxm1 from airway club cells decreased goblet cell metaplasia caused by house dust mite allergens. While FOXM1 is increased in human COPD and mouse genetic data suggest that FOXM1 is critical goblet cell metaplasia, pulmonary inflammation and alveolar remodeling, molecular mechanisms regulated by FOXM1 in COPD remain unknown. We propose to test the hypothesis that FOXM1 increases goblet cell metaplasia and emphysema in COPD by transcriptionally activating distinct sets of pro-inflammatory and mucinous genes in alveolar type II cells, airway club cells and macrophages. We will also test the therapeutic efficacy of novel FOXM1 inhibitor RCM-1 in mouse and rat COPD models. Chronic CS exposure and a combination of CS and Influenza infection will be used to induce pulmonary inflammation, emphysema and goblet cell metaplasia. In Aim 1, we will identify molecular mechanisms regulated by FOXM1 in alveolar type II cells (Aim 1A) and macrophages (Aim 1B) using purified cells and mice with specific ablation of Foxm1 gene from these cell types. FOXM1 targets will be validated using de-identified human COPD lungs. In Aim 2A, we will use mice with specific deletion of Foxm1 from airway club cells, to identify FOXM1 target genes critical for differentiation of club cells into goblet cells in COPD model. In Aim 2B, we will test therapeutic potential of novel, non-toxic FOXM1-inhibiting small molecule compound, RCM-1, which has been recently discovered in my lab using a high throughput screen. Altogether, these studies will identify novel molecular mechanisms critical for COPD pathogenesis and test therapeutic potential of FOXM1 inhibitors in animal COPD models.

项目总结。慢性阻塞性肺病是一种严重的慢性呼吸系统疾病，与吸烟和吸烟有关