Chronic obstructive pulmonary disease (COPD) is the third leading cause of chronic morbidity and mortality, both in the United States (affecting an estimated 23 million people) and globally. Cigarette smoke (CS), the most important etiological risk factor for the development of COPD, has been shown to cause DNA damage and cellular senescence, leading to premature and accelerated lung aging. The molecular mechanisms that lead to DNA damage and cellular senescence, however, as well as their roles in the development of COPD/emphysema are not known. Our preliminary data show that histone deacetylase 2 (HDAC2) level is significantly decreased in lung epithelial cells, fibroblasts and lungs of mice exposed to CS. This reduction is associated with specific changes in histone H3 acetylation and methylation. Furthermore, mice deficient in HDAC2 exhibit augmented DNA damage, impaired DNA non-homologous end joining (NHEJ) repair, cellular senescence and inflammatory response in lungs in response to CS exposure. However, no information is available regarding the role of HDAC2 in DNA damage/repair, stress-induced premature senescence (SIPS), or senescence-associated secretory phenotype (SASP), particularly in response to CS exposure in the lung. We hypothesize that CS causes persistent DNA damage and impairs NHEJ via HDAC2-dependent chromatin modifications, thereby leading to SIPS and SASP, and to subsequent pulmonary emphysema. To test this hypothesis, we plan to pursue the following three Specific Aims. (1) To determine whether CS-mediated DNA damage and NHEJ impairment lead to SIPS and SASP via HDAC2 reduction. Here, we will test the hypothesis that NHEJ becomes less efficient and DNA damage is increased when HDAC2 is reduced in response to CS exposure, leading to lung cellular SIPS and SASP. (2) To determine HDAC2-dependent chromatin mechanisms that underlie CS-mediated DNA damage, SIPS and SASP. We will investigate the role of HDAC2-regulated specific histone H3 modifications (acetylation and methylation) in DNA damage and repair in the lung. (3) To determine the involvement of DNA damage-mediated SIPS and SASP via HDAC2 reduction in development of pulmonary emphysema. We hypothesize that HDAC2 reduction contributes to epigenomic instability and subsequent emphysema due to SIPS and SASP. The outcome of this proposal will not only unravel HDAC2-dependent epigenetic chromatin mechanisms underlying DNA damage-induced senescence, but also provide understanding of the role of SIPS and SASP in the development of COPD/emphysema. Overall, these studies will have translational potential to identify novel therapeutic targets in ameliorating premature lung aging in COPD.
Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of chronic morbidity and mortality in the United States, and thus represents a major public health concern. COPD is linked to premature and accelerated aging of the lungs due to cigarette smoking. Our research will unravel key mechanisms in lung irreversible cellular growth arrest and DNA damage which will allow us to identify therapeutic targets and to develop novel therapeutic strategies to prevent the premature aging of the lung in the development of COPD-emphysema.
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