Chronic obstructive pulmonary disease (COPD) is an abnormal inflammatory airway disease with systemic inflammation and manifestations, currently lacking effective treatment to modify its progression and to decrease mortality. This is partly due to insensitive of the inflammation to glucocorticoids (GCs). It has been known that reduced histone-deacetylase 2 (HDAC2), in amount and activity contribute to the abnormal inflammation and GC-insensitivity. Reduced SIRT2, another HDAC, has also been implicated in the inflammation. However, HDAC2 and SIRT2 could not explain all the inflammation of the disease. In addition, other pathogenesis includes premature aging process, apoptosis, DNA damage, impairment in microbial defense are also implicated in this disease. Further exploration into the molecular mechanism is emergent for developing effective treatment. We has reported that NF-κB repressing factor (NRF), an endogenous repressor of the pivotal inflammatory transcription factor NF-κB-response genes, is reduced in peripheral blood mononuclear cells (PBMC) of COPD patients, which is a link toward systemic inflammation of COPD. During continue working on COPD inflammation, we have preliminary data indicated that the repressive epigenetic enzyme SUV39H1, which catalyze histone H3K9 di- and tri-methylation, is reduced in COPD PBMC. In addition to play a major role in heterochromatin formation, this protein is involved in Th1/Th2 gene balance, suppression of a few known inflammatory genes, genome stability and anti-aging process. We also found that SIRT1, which has been reported to protect SUV39H1 in response to oxidative stress. We therefore hypothesized that defect in SUV39H1 negative regulatory mechanism leads to abnormal inflammation, GS insensitivity and DNA instability in COPD. Reduced SIRT1, at least in part, contributes to defect in SUV39H1. This is a 3-year project with 4 specific aims: (1), to study the clinical relevance of SUV39H1 and SIRT1 in patients with COPD; (2), to confirm the role of SUV39H1 in control of inflammation, DNA damage and in steroid anti-inflammatory effects; (3), to explore the mechanisms whereby SUV39H1 is down regulated in COPD PBMC; (4), to investigate the role of SUV39H1 in COPD animal models. We will enroll 180 subjects, including 30 each of normal non-smokers, healthy smokers and stage I-IV COPD patients. SIRT1/SUV39H1 and the related molecules will be correlated to the clinical data. PBMC, monocyte cell lines and respiratory epithelial cell lines will be used to explore the mechanism. BALB/c mice exposed to cigarette smoke using a cigarette smoke chamber will be used as animal models. This study will not only advance our knowledge into the mechanism whereby abnormal inflammation, glucocorticoids insensitivity and DNA instability are induced, but also will possibly provide new biomarkers and a novel therapeutic direction for developing effective therapy for COPD.
|Effective start/end date||8/1/15 → 7/31/16|
- steroid insensitivity
- DNA instability
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