Chronic obstructive pulmonary disease (COPD) is a chronic lung disease that is incurable and typically progressive. Chronic bronchitis and emphysema are the predominant examples of COPD. Most people diagnosed with COPD have both chronic bronchitis and emphysema. COPD is a leading cause of death worldwide, and its prevalence is increasing in industrial countries. Symptoms of COPD include shortness of breath, chronic persistent coughing, chronic coughing that produces excessive amounts of mucus, chest tightness, and wheezing, among other symptoms. On a tissue level, inflammation, cell death and extensive lung tissue remodeling characterize COPD. The intensity of the inflammatory responses and the alterations in cell behavior reflect both the activation state of the signaling proteins upstream of the genes of interest and the signal-induced assembly of nuclear chromatin complexes that support the formation of mRNA. Specifically, in COPD, an alteration in gene expression result both from the activation of key transcription factors and from the epigenetic changes that affect chromatin remodeling (e.g., altered histone acetylation). Nuclear chromatin, which includes several histones, is the cell scaffolding that promotes the interaction between DNA and the transcription factors which affect gene expression. Of interest, however, is that histones also exert diverse functions when present extracellularly. Moreover, while histones are not generally believed to be noxious, they induce lung inflammation and damage when present in the circulation and are cytotoxic to the human lung cells when present in the extracellular space. Our recent data support the mechanism that one of the histone variants, H3.3, is elevated in the lumen of lung airways of COPD subjects and that it cytotoxic to other alveolar cells via the dysregulation of calcium homeostasis. However, the mechanism and consequences of extracellular H3.3 cytotoxicity have not been fully examined in COPD. Our goal is to determine whether an increase in extracellular H3.3 can be used to predict the rate of the disease’s progression, whether H3.3 can induce severe disease in an animal model, and to investigate the mechanism of H3.3 in COPD progression by identifying the interacting membrane partners responsible for triggering cell death.
Moulder Center for Drug Discovery Research
Temple University School of Pharmacy
3307 N Broad Street
Philadelphia, PA 19140