Thursday, November 21, 2024
11/21/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
