Lung development is a precise and specific process that continues after birth. Perturbations in this signaling may lead to alterations in lung structue and function in postnatal life with long lasting consequences. The response of neonatal mice exposed to high concentrations of oxygen postnatally resembles the characteristic pathological events of BPD. Within a few days, cell proliferation, lung volume and pulmonary compliance are decreased. The stress protein heme oxygenase (HO)-1 regulates cellular heme degradation and heme is a key ligand for the nuclear receptor Rev-ERB?. This gene is a key modulator of the circadian rhythm and is a master regulator of cellular proliferation and metabolism. The role of the circadian rhythm in neonatal lung tissues has not yet been described. Because Rev-ERB? expression is under the control of heme, we will evaluate how HO-1 may alter Rev-ERB? expression and determine whether this helps to explain the well-known cytoprotective effects of HO-1 in hyperoxia. We have recently observed that in neonatal lungs and in cultured cells exposed to hyperoxia, protein levels for Rev-ERB? are decreased. We will also determine how Rev-ERB? expression is regulated by hyperoxia in neonatal mouse lungs and whether it is key to modulating hyperoxic injury and repair. Using mutant mice with disruption or over-expression of a stabilized Rev-ERB? protein, we will assess whether the expression of Rev-ERB? can mitigate hyperoxia-mediated lung injury and subsequent repair. A clear understanding of the role and relevance of Rev-ERB? in the neonatal lung will allow us to devise therapeutic strategies to obviate neonatal lung hyperoxic injury and assure coordinated repair.

Public Health Relevance

Infants born prematurely are often exposed to high concentrations of oxygen (hyperoxia) and this leads to lung injury referred to as bronchopulmonary dysplasia (BPD). This condition leads to long-term sequelae including neurodevelopmental delay. This proposal will address how lung heme oxygenase (HO)-1; the rate limiting enzyme in heme degradation affects the circadian regulating protein Rev-ERB resulting in protection against hyperoxia. These insights may lead to important therapeutic strategies to prevent lung oxidative stress.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Laposky, Aaron D
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Children's Hospital of Philadelphia
United States
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Sengupta, Shaon; Yang, Guang; O'Donnell, John C et al. (2016) The circadian gene Rev-erb? improves cellular bioenergetics and provides preconditioning for protection against oxidative stress. Free Radic Biol Med 93:177-89
Dennery, Phyllis A (2014) Signaling function of heme oxygenase proteins. Antioxid Redox Signal 20:1743-53
Dennery, Phyllis A (2014) Heme oxygenase in neonatal lung injury and repair. Antioxid Redox Signal 21:1881-92
Yang, Guang; Wright, Clyde J; Hinson, Maurice D et al. (2014) Oxidative stress and inflammation modulate Rev-erb? signaling in the neonatal lung and affect circadian rhythmicity. Antioxid Redox Signal 21:17-32