Inflammation in the CF lung has been shown to be excessive, and slow to resolve. Typically this leads to lung damage, eventual lung failure and is the lead cause of mortality. A number of studies have reported that CF cells, especially airway epithelia produce abnormal levels of inflammatory cytokines in response to inflammatory stimuli. Anti-inflammatory therapy that controls inflammatory signaling has been shown to be beneficial, slowing lung deterioration in patients, and is perhaps one of the best therapies for CF. Therefore, delineating the mechanisms of inflammation in CF, which can yield targets for anti-inflammatory therapy, is an important and worthwhile effort. Furthermore, it is logical to suspect that downstream mechanisms that contribute to inflammation in the CF lung are also present in other inflammatory lung diseases, such COPD and Asthma, increasing the significance of studying aberrant inflammatory signaling in CF. However, neither the mechanisms that promote nor those that limit inflammatory responses are well understood. Recent studies by us have elucidated a dysregulation of the antioxidant response element (ARE) transcription factor, Nrf2, in multiple in vitro and in vivo models of CF. Although CF cells exhibit oxidative stress, Nrf2 protective cascades are not activated and are in fact decreased. This results in the accumulation of intracellular oxidants, which significantly increases inflammatory cytokine production and reduces the activity of pathways that resolve inflammation. This is an important finding as Nrf2 has been implicated in a number of inflammatory lung diseases and can be safely and specifically activated, and is therefore a viable therapeutic target. Rescue of Nrf2 dysfunction in CF epithelial cells reduces inflammatory responses to normal levels, but does not inhibit normal responses, which would be deleterious in the context of CF. In this application we propose to examine the regulation of Nrf2 activity in CF primary epithelial cells, CF animal models, and tissues from CF patients. We plan to: 1) To determine the step or steps in the Nrf2 activation cascade that are dysfunctional in CF;2) To examine the mechanism by which CFTR dysfunction results in the dysregulation of Nrf2;and 3) To test pharmacological agents which activate Nrf2 by different mechanisms to elucidate potential therapies for Nrf2 dysfunction. These studies have the potential to delineate the link between CFTR dysfunction and inflammation in CF, and define novel therapeutic targets. Furthermore, our studies extend to mechanisms of inflammation and disease observed in cardiac (foam cell formation and arthrosclerosis), pulmonary (chronic obstructive pulmonary disease and asthma), and neurological (Niemann-Pick and Parkinson's disease) disorders. Therefore, our findings may illuminate mechanisms relevant to a wide range of disorders.
The premise of this application is that CFTR dysfunction results in cell signaling responses that diminish the activity of Nrf2, a transcription factor that modulates redox balance in cells. Preliminary data demonstrate that loss of CFTR function results in Nrf2 dysfunction which significantly contributes to inflammatory signaling in epithelial cells, and that correction of Nrf2 dysregulation provides a markedly effective and specific anti- inflammatory benefit. The goal of this study is to characterize the mechanisms that lead to Nrf2 dysfunction and the impact of these mechanisms on disease-causing inflammatory signaling.
|Ostrowski, Stephen M; Johnson, Kachael; Siefert, Matthew et al. (2016) Simvastatin inhibits protein isoprenylation in the brain. Neuroscience 329:264-74|
|Rymut, Sharon M; Ivy, Tracy; Corey, Deborah A et al. (2015) Role of Exchange Protein Activated by cAMP 1 in Regulating Rates of Microtubule Formation in Cystic Fibrosis Epithelial Cells. Am J Respir Cell Mol Biol 53:853-62|
|Chirkova, Tatiana; Lin, Songbai; Oomens, Antonius G P et al. (2015) CX3CR1 is an important surface molecule for respiratory syncytial virus infection in human airway epithelial cells. J Gen Virol 96:2543-56|
|Ziady, Assem G; Hansen, Jason (2014) Redox balance in cystic fibrosis. Int J Biochem Cell Biol 52:113-23|
|Cheng, Yu; Doane, Tennyson L; Chuang, Chi-Hung et al. (2014) Near infrared light-triggered drug generation and release from gold nanoparticle carriers for photodynamic therapy. Small 10:1799-804|
|Voit, Eberhard O (2014) Mesoscopic modeling as a starting point for computational analyses of cystic fibrosis as a systemic disease. Biochim Biophys Acta 1844:258-70|
|Ziady, Assem G; Sokolow, Andrew; Shank, Samuel et al. (2012) Interaction with CREB binding protein modulates the activities of Nrf2 and NF-ÎºB in cystic fibrosis airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 302:L1221-31|
|Drumm, Mitchell L; Ziady, Assem G; Davis, Pamela B (2012) Genetic variation and clinical heterogeneity in cystic fibrosis. Annu Rev Pathol 7:267-82|