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

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。COPD是一种严重的慢性呼吸道疾病，与吸烟和以慢性肺部炎症、肺气肿、呼吸道重塑和杯状细胞化生为特征。需要确定新的分子靶点来改善COPD患者的治疗结果。我们的赠款应用将探索Forkhead转录因子FOXM1作为潜在治疗靶点的作用建立小鼠和大鼠COPD模型。FOXM1是一种胚胎转录因子，不表达于肺静止，但在肺癌发生过程中诱发异常。我们提供了初步的数据演示慢性阻塞性肺疾病患者和小鼠呼吸道上皮细胞、巨噬细胞和II型细胞中FOXM1被激活暴露在香烟烟雾中(CS)。FOXM1在小鼠和人肺中的表达增加相关伴有肺气肿和杯状细胞化生。FOXM1在肺泡II型细胞中的转基因过表达加重肺部炎症，导致肺气肿。髓系细胞FOXM1基因的遗传缺失包括巨噬细胞和单核细胞，可减轻急性肺损伤后的肺部炎症。遗传去除呼吸道俱乐部细胞FOXM1可减少室内尘螨引起的杯状细胞化生过敏原。虽然FOXM1在人类COPD和小鼠中增加，但遗传数据表明FOXM1是关键杯状细胞化生、肺部炎症和肺泡重塑 FOXM1在COPD中的作用尚不清楚。我们建议检验FOXM1增加杯状细胞的假设 COPD患者的化生和肺气肿通过转录激活不同的促炎和肺泡II型细胞、气道俱乐部细胞和巨噬细胞中的粘液基因。我们还将测试治疗方法新型FOXM1抑制剂RCM-1对COPD小鼠和大鼠模型的疗效。慢性CS暴露和a CS和流感感染的组合将导致肺部炎症、肺气肿和杯状细胞化生。在目标1中，我们将确定FOXM1在肺泡II型中调节的分子机制使用纯化细胞和特异性去除FOXM1基因的小鼠的细胞(Aim 1A)和巨噬细胞(Aim 1B) 从这些细胞类型中。FOXM1目标将使用未识别的人类COPD肺进行验证。在目标2 A中，我们将使用从呼吸道俱乐部细胞中特异缺失FOXM1的小鼠，以确定FOXM1关键的靶基因慢性阻塞性肺疾病模型中俱乐部细胞向杯状细胞分化的实验研究在目标2B中，我们将测试治疗潜力新型无毒FOXM1抑制小分子化合物RCM-1，最近在我的实验室使用的是高通量屏幕。总之，这些研究将确定新的分子机制。 FOXM1抑制剂在动物COPD模型中对COPD发病机制和治疗潜力的测试至关重要。