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Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the United States, claiming 126,005 American lives in the year of 2005. More than 12 millions of people are currently diagnosed with COPD, with possibly an additional 12 millions of people having the disease without knowing it. COPD is a general term which includes two conditions: chronic bronchitis, persistent inflammation of the airways of the lung, and emphysema, damage to the smaller airways and airsacs of the lungs. Chronic bronchitis or emphysema can cause narrowing of the airways, resulting in breathing difficulty. Tobacco smoking is the cause in the vast majority of COPD cases, as the lining of the airways becomes inflamed and damaged by smoking. People who have never smoked rarely develop COPD. Currently, there is no treatment that can reverse the damage to the airways, thus no known cure of COPD. Because inflammation plays a vital role in the development and progression of COPD, reducing inflammation in lung is an effective approach. Glucocorticoids, a.k.a. corticosteroids, are often included as part of the treatment for COPD patients due to its ability to suppress inflammation. However, long-term glucocorticoids treatment could cause side effects such as osteoporosis, muscle atrophy, and various metabolic disorders. In addition, glucocorticoids¡¦ anti-inflammatory efficacy is greatly reduced in COPD patients comparing its effectiveness seen in other diseases, such as asthma and arthritis. Glucocorticoids convey their signals through a protein that is localized inside the cells called glucocorticoid receptor (GR). It is believed that GR suppresses inflammation by turning off inflammatory genes and, at higher dose, turning on anti-inflammatory genes. Inflammatory genes are turned on by a protein called necrosis factor-kappa B (NF-£eB). Studies have suggested that GR can counteract the inflammatory effect of NF-£eB through recruitment of another protein, histone deacetylase-2 (HDAC2). However, the detailed mechanism of this process is unknown. In this proposal, I will investigate how GR recruits HDAC2 to inhibit NF-£eB action. I will also examine the entire human genome to learn whether HDAC2 is generally required for GR to inhibit NF-£eB-regulated genes, or this mechanism is only for specific subset of NF-£eB-regulated genes. Overall, it is important to explore the mechanism of glucocorticoids¡¦ anti-inflammatory action, as it could reveal new therapeutic target, as well as improve drug designing. In addition, recent studies have shown that HDAC2 level is reduced in COPD patients, which could explain the glucocorticoid resistant phenotype found in COPD patients. My proposed study of GR and HDAC2 connection will shed new light onto this critical issue, and shall specifically benefit the future therapeutic development for COPD. |
