PROJECT SUMMARY
Cystic Fibrosis (CF) has been a pediatric disease, but with improved treatment and care it has
become a chronic disease extending the life expectancy of patients. The characteristic chronic
pro-inflammatory process in CF accelerates cellular senescence and further complicates this
disease. Therefore, novel therapeutic strategies are needed to combat cellular senescence in the
CF lung. Cellular senescence is a key process underlying aging, which leads to an accumulation
of epigenetic noise. Such noise distorts the epigenetic landscape and dysregulates gene
expression, resulting in declined tissue function and age-related diseases. We and others have
established that epigenetics are involved in the pathogenesis of age-related diseases. We have
shown that anti-aging methods improve mucociliary clearance in the CF bronchial epithelium.
Cellular senescence is regulated via gene transcription through the interplay between promoters,
enhancers, and cis-acting regulatory elements bound by transcription factors. Bromodomain-
containing protein 4 (Brd4) is an epigenetic reader protein. It binds to acetylated histone and
recruits transcriptional factors for actively transcribed genes. Transcription factor AP-1 was
recently reported to mark the senescence enhancer landscape and drive the transcriptional
program in senescent cells. Brd4 is critical for many senescence-associated secretory phenotype
related inflammatory gene expression profiles. However, the role of Brd4 and its interactions with
AP-1 to control the senescent related gene expression in the CF bronchial epithelium has not
been explored. Our preliminary data showed that blocking Brd4 down-regulated multiple
senescent genes, and reduced the recruitment of AP-1 to those genes. We hypothesize that
blocking Brd4 in the CF bronchial epithelium will epigenetically reduce cellular senescence in the
CF lung ultimately preserving lung function. To test our hypothesis, we will first determine if Brd4
regulates the chromatin accessibility and is required for senescent-related gene expression in the
CF bronchial epithelium; we will also explore the underlying mechanisms and the interactions of
Brd4 and AP-1 in regulating senescent related gene expression; lastly, we will determine the
efficacy of Brd4 inhibition in CFTR responsive and unresponsive CF rat models. Results from this
study will offer new insights of epigenetic regulation in the CF bronchial epithelium and provide
support for targeting senescent airway cells in CF lung disease as a novel therapeutic strategy.