Our approach in elucidating critical pathways involved in the pathogenesis of human COPD has been to identify candidate genes from a comprehensive study of regulated genes in human lung tissues of individuals with COPD. We performed comprehensive gene expression profiling by means of SAGE and microarray analysis to examine differential gene expression patterns and identify candidate genes in human lung tissues of individuals with COPD (GOLD 2) compared with that of smokers without airflow obstruction. Among the many significant genes markedly regulated in our analysis, we have chosen to focus on early growth response-1 (Egr-1). The rationale for focusing on Egr-1 is based on several critical factors including: 1) EGR-1 was not only one of the 327 expressed genes significantly regulated in COPD tissues, but also ranked at the top of sequences tag hits among the genes we validated and confirmed in our SAGE analysis;2) Egr-1 regulates key effector molecules critical in the established pathways and paradigms currently governing COPD including apoptosis, inflammation, oxidant/antioxidant balance, proteases/anti-proteases, and immune functions;3) Our in vitro and in vivo preliminary studies demonstrate that cigarette smoke in both in vivo and in vitro regulate Egr-1 expression. We will use both in vitro and in vivo models to test the hypothesis that Egr-1 acts as a critical upstream master switch molecule in regulating apoptosis and inflammation in COPD. We will also examine how Egr-1 regulates adaptive and stress responses to defend against the apoptotic and inflammatory processes, and will test the hypothesis that Egr-1 regulated heme oxygenase (HO)-1 helps counter balance against the apoptotic and inflammatory processes to achieve homeostasis in pathophysiologic disorders such as COPD Hence, we will test our hypothesis by addressing the following specific aims:
Specific Aim 1. Test the hypothesis that Egr-1 can regulate apoptosis, both intrinsic and extrinsic apoptotic pathways, following cigarette smoke in vitro and in vivo.
Specific Aim 2. Test the hypothesis that Egr-1 can regulate inflammatory process, both chemokine and cytokine expression, following cigarette smoke exposure in vitro and in vivo.
Specific Aim 3. Test the hypothesis that Egr-1 regulated HO-1 expression can provide potent anti-apoptotic and anti-inflammatory effects, critical in the adaptive and stress response of cytoprotection against cigarette smoke. PROJECT NARRATIVE. The molecular basis of cigarette smoke induced COPD is poorly understood. We will attempt to examine specific molecular pathways which plays critical role in the pathogenesis of COPD. These pathways will potentially target new therapeutic modality in the future for the treatment of patients with COPD.
| Nakahira, Kiichi; Haspel, Jeffrey Adam; Rathinam, Vijay A K et al. (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222-30 |
