PROJECT SUMMARY. COPD is a severe chronic respiratory disease which is associated with smoking andcharacterized 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 grantapplication will explore the role of Forkhead transcription factor FOXM1 as a potential therapeutic target inmouse and rat COPD models. FOXM1 is an embryonic transcription factor which is not expressed inquiescent lungs but aberrantly induced during lung carcinogenesis. We provide preliminary data demonstratingthat FOXM1 is activated in airway epithelial cells macrophages and type II cells of COPD patients and miceexposed to cigarette smoke (CS). Increased expression of FOXM1 in mouse and human lungs is associatedwith emphysema and goblet cell metaplasia. Transgenic overexpression of FOXM1 in alveolar type II cellsexacerbated lung inflammation leading to emphysema. Genetic deletion of Foxm1 gene from myeloid cellsincluding macrophages and monocytes decreased pulmonary inflammation after acute lung injury. Geneticablation of Foxm1 from airway club cells decreased goblet cell metaplasia caused by house dust miteallergens. While FOXM1 is increased in human COPD and mouse genetic data suggest that FOXM1 is criticalgoblet cell metaplasia pulmonary inflammation and alveolar remodeling molecular mechanisms regulated byFOXM1 in COPD remain unknown. We propose to test the hypothesis that FOXM1 increases goblet cellmetaplasia and emphysema in COPD by transcriptionally activating distinct sets of pro-inflammatory andmucinous genes in alveolar type II cells airway club cells and macrophages. We will also test the therapeuticefficacy of novel FOXM1 inhibitor RCM-1 in mouse and rat COPD models. Chronic CS exposure and acombination of CS and Influenza infection will be used to induce pulmonary inflammation emphysema andgoblet cell metaplasia. In Aim 1 we will identify molecular mechanisms regulated by FOXM1 in alveolar type IIcells (Aim 1A) and macrophages (Aim 1B) using purified cells and mice with specific ablation of Foxm1 genefrom these cell types. FOXM1 targets will be validated using de-identified human COPD lungs. In Aim 2A wewill use mice with specific deletion of Foxm1 from airway club cells to identify FOXM1 target genes critical fordifferentiation of club cells into goblet cells in COPD model. In Aim 2B we will test therapeutic potential ofnovel non-toxic FOXM1-inhibiting small molecule compound RCM-1 which has been recently discovered inmy lab using a high throughput screen. Altogether these studies will identify novel molecular mechanismscritical for COPD pathogenesis and test therapeutic potential of FOXM1 inhibitors in animal COPD models.