Friday, November 22, 2024
11/22/2024
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.
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