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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.

项目摘要。COPD是一种严重的慢性呼吸道疾病，与吸烟和其特征在于慢性肺部炎症、肺气肿、气道重塑和杯状细胞化生。需要鉴定新的分子靶点以改善COPD患者的治疗结果。我们的资助应用将探索叉头转录因子FOXM 1作为潜在治疗靶点的作用，小鼠和大鼠COPD模型。FOXM 1是一种胚胎转录因子，在胚胎发育中不表达。静止的肺，但在肺癌发生过程中异常诱导。我们提供的初步数据表明， FOXM 1在COPD患者和小鼠的气道上皮细胞、巨噬细胞和II型细胞中被激活，香烟烟雾（CS）。小鼠和人肺中FOXM 1表达增加与肺气肿和杯状细胞化生肺泡II型细胞中FOXM 1的转基因过表达加剧了肺部炎症导致肺气肿骨髓细胞中Foxm 1基因的遗传缺失，包括巨噬细胞和单核细胞，减少急性肺损伤后的肺部炎症。遗传去除气道俱乐部细胞Foxm 1减少屋尘螨引起的杯状细胞化生过敏原虽然FOXM 1在人类COPD中增加，但小鼠遗传数据表明FOXM 1是至关重要的。杯状细胞化生，肺部炎症和肺泡重塑， FOXM 1在COPD中的作用尚不清楚。我们建议测试FOXM 1增加杯状细胞的假设，通过转录激活不同的促炎性和肺泡II型细胞、气道俱乐部细胞和巨噬细胞中的粘液基因。我们还将测试新型FOXM 1抑制剂RCM-1在小鼠和大鼠COPD模型中功效。慢性CS暴露和 CS和流感病毒感染的组合将用于诱导肺部炎症、肺气肿和杯状细胞化生在目标1中，我们将确定II型肺泡中FOXM 1调节的分子机制细胞（Aim 1A）和巨噬细胞（Aim 1B），使用纯化的细胞和小鼠特异性切除Foxm 1基因这些细胞类型。FOXM 1靶标将使用去识别的人COPD肺进行验证。在目标2A中，我们将使用从气道俱乐部细胞中特异性缺失Foxm 1的小鼠，以鉴定FOXM 1靶基因， COPD模型中棒状细胞向杯状细胞的分化。在目标2B中，我们将测试一种新的、无毒的FOXM 1抑制小分子化合物，RCM-1，最近在我的实验室用的是高通量筛选。总之，这些研究将确定新的分子机制，关键的COPD发病机制和测试FOXM 1抑制剂在动物COPD模型中的治疗潜力。