Secretory mucin glycoproteins are the major macromolecular component of lung mucus, which coats and protects the respiratory tract. Mucins are hypersecreted and overproduced in acute and chronic lung disease, thereby contributing to mucus obstruction in the airways and to disease morbidity and mortality in patients with asthma and other chronic obstructive pulmonary diseases. MUC5AC, one of the major airway mucins, is localized to goblet cells in the conducting airway epithelium, and is overexpressed in asthmatic airways. Our long term objective is to better define the link between activation and repression of MUC5AC mucin gene expression at the molecular level in order to provide a better foundation for developing novel pharmaceutical agents to circumvent mucin overproduction. The MUC5AC gene can be transcriptionally activated (IL-1?) or repressed (Dex) in lung cells in a pathologically and pharmacologically relevant fashion. However, little is known about mechanisms that regulate mucin gene cis-repression, which likely involve remodeling of chromatin, a higher level of gene regulation, or about chromatin modification of mucin genes. In this application, we will focus on Dex-mediated chromatin remodeling in cis- repression of MUC5AC gene expression and on IL-1?-induced chromatin modifications in upregulating MUC5AC gene expression. We will investigate mechanisms underlying these events in lung cells in three Aims. They will be evaluated in vitro in differentiated NHBE cells and A549 cells and in vivo in a murine model of allergic asthma and in human tissue.
In Aim 1 we will characterize the GR-induced cis-repression of MUC5AC at the chromatin level to test the hypothesis that Dex cis-represses MUC5AC gene expression by chromatin remodeling.
In Aim 2 we will characterize the IL-1?-induced activation of the MUC5AC gene to test the hypothesis that the MUC5AC gene belongs to a class of genes with promoters with regulated and late accessibility, e.g. promoters that require stimulus-dependent modifications in chromatin structure to make transcription factors sites accessible for transcription.
In Aim 3 we will determine whether inflammatory mediators (IL-1?) and anti-inflammatory agents (Dex) mediate opposing effects on MUC5AC chromatin structure in lung cells exposed to both mediators. This would ultimately impact on MUC5AC mucin production during corticosteroid treatment of inflammatory lung disease.
. Mucins are hypersecreted and overproduced in chronic lung disease, thereby contributing to mucus obstruction in the airways and to disease morbidity and mortality in patients with asthma and other chronic obstructive pulmonary diseases. MUC5AC is a major lung mucin and is overproduced in asthmatic airways. The MUC5AC gene has been shown to be transcriptionally activated (IL-1?) or repressed (Dex) in lung cells in a pathologically and pharmacologically relevant fashion. Understanding the mechanisms whereby MUC5AC gene expression is repressed by glucocorticoids will prove useful in understanding why steroid maintenance is important in reducing the number and severity of exacerbations in severe asthmatic patients and is fundamental for formulating therapeutic interventions in lung diseases with mucin overproduction.
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