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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：
10170416
负责人：
Vladimir Kalinichenko
金额：
$ 56万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170416
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 Airway 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 Lung Inflammation Lung diseases 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 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/antagonist 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。慢性阻塞性肺病（COPD）是一种严重的慢性呼吸道疾病，与吸烟和吸烟有关其特征为慢性肺部炎症、肺气肿、气道重塑和杯状细胞化生。需要确定新的分子靶点来改善慢性阻塞性肺病患者的治疗结果。我们的资助该应用将探索 Forkhead 转录因子 FOXM1 作为潜在治疗靶点的作用小鼠和大鼠慢性阻塞性肺病模型。 FOXM1 是一种胚胎转录因子，不表达于静止的肺，但在肺癌发生过程中异常诱导。我们提供初步数据证明 COPD 患者和小鼠的气道上皮细胞、巨噬细胞和 II 型细胞中 FOXM1 被激活暴露于香烟烟雾（CS）。 FOXM1 在小鼠和人类肺部表达的增加与伴有肺气肿和杯状细胞化生。 FOXM1 在 II 型肺泡细胞中转基因过表达加剧肺部炎症，导致肺气肿。骨髓细胞中 Foxm1 基因的遗传删除，包括巨噬细胞和单核细胞，可减少急性肺损伤后的肺部炎症。遗传去除气道俱乐部细胞中的 Foxm1 可减少屋尘螨引起的杯状细胞化生过敏原。虽然 FOXM1 在人类 COPD 中增加，但小鼠遗传数据表明 FOXM1 至关重要杯状细胞化生、肺部炎症和肺泡重塑、调控的分子机制 FOXM1 在 COPD 中的作用仍不清楚。我们建议检验 FOXM1 增加杯状细胞的假设 COPD 中的化生和肺气肿是通过转录激活不同组的促炎和肺气肿来实现的。肺泡 II 型细胞、气道俱乐部细胞和巨噬细胞中的粘液基因。我们还将测试治疗效果新型 FOXM1 抑制剂 RCM-1 在小鼠和大鼠 COPD 模型中的功效。慢性CS暴露和 CS和流感感染的结合将导致肺部炎症、肺气肿和杯状细胞化生。在目标 1 中，我们将确定 FOXM1 在 II 型肺泡中调节的分子机制细胞 (Aim 1A) 和巨噬细胞 (Aim 1B)，使用经过 Foxm1 基因特异性消融的纯化细胞和小鼠来自这些细胞类型。 FOXM1 靶标将使用未识别的人类 COPD 肺部进行验证。在目标 2A 中，我们将使用从气道俱乐部细胞中特异性删除 Foxm1 的小鼠来识别对疾病至关重要的 FOXM1 靶基因 COPD模型中棒状细胞分化为杯状细胞。在目标 2B 中，我们将测试以下药物的治疗潜力：新型、无毒的 FOXM1 抑制小分子化合物 RCM-1，最近在我的实验室使用高通量屏幕。总而言之，这些研究将确定新的分子机制对 COPD 发病机制至关重要，并测试 FOXM1 抑制剂在动物 COPD 模型中的治疗潜力。