Role and regulation of heme oxygenase in the neonatal lung.
Developmental differences in response to oxidative stress.
Key words: heme oxygenase, oxidative stress, neonatal, lung, gene regulation, transcription factor, circadian.
Description of Research
Neonates are relatively less susceptible to oxidative stress but suffer long term consequences including chronic lung disease. My laboratory investigates the role and regulation of heme oxygenase-1 (HO-1) in neonatal lung antioxidant defenses. We have shown that over-expression of HO-1 is cytoprotective however, beyond a certain threshold in the lung, there are detrimental effects associated with HO-1. This may be related to other non-enzymatic functions of the HO-1 protein. We have shown that HO-1 protein, devoid of activity can alter cellular signaling and migrate to the nuclear compartment. This mechanism involves a proteolytic cleavage at the C-terminus of the protein. We are currently defining the role of this cleaved protein as a modulator of DNA repair as it binds to various DNA repair proteins to modulate their activity.
We are particularly focusing on the effects of HO-1 in postnatal lung development using murine models with disruption of HO-1 or transgenics over-expressing the HO-1 15 kB promoter drivng the expression of luciferase. Due to the availability of an In vitro imaging system, HO-1 gene expression can be monitored in vivo in real time. This technology along with standard molecular, proteinomic, genomic and histological techniques allows us to answer the questions relating to the role of HO-1 in the developing lung. Other interests are in the role of transcription factors including NF-kB and C-EBPx for neonatal lungs oxidative susceptibility. A recent project is evaluating the circadian rhythm gene Rev-erbx and its role in lung function in response to oxidative stress and its regulation by NF-kB.
1. Define specific pathways for HO-1 DNA repair protein interactions
2. Epigenetic regulation of HO-1 gene expression
3. Hyperoxia regulation of Rev-erbx in the neonatal lung
Guang Yang, Ph.D. - Lab manager
Maurice Hinson, B.S. - Research Assistant
Patrick Fernando, M.D. - Research Assistant
Funihiko Namba - Post-doctoral Fellow
- Associate Professor of Pediatrics at University of Pennsylvania School of Medicine (2003 – 2006)
- Professor of Pediatrics at University of Pennsylvania School of Medicine (2006 – 2015)
- MD, Howard University (1984)
- BSc, Biology-Genetics, McGill University (1980)
- Wright CJ, Zhuang T, La P, Yang G, Dennery PA. Hyperoxia-induced NF-kB activation occurs via a maturationally sensitive atypical pathway. Am J Physiol Lung Cell Mol Physiol. Vol 296(3) . 2008:L296-L306.
- Lin Q, Weis S, Yang G, Zhuang T, Abate A, Dennery PA. Catalytic inactive heme oxygenase-1 protein regulates its own expression in oxidative stress. Free Radic Biol Med. Vol 44(5) . 2008:847-855.
- Dennery PA. Effects of oxidative stress on embryonic development. Birth Defects Research Part C. Birth Defects Res C Embryo Today. Vol 81(3) . 2007:155-162.
- Alvira CM, Abate A, Yang G, Dennery PA, Rabinowich M. NF-kB activation in the neonatal mouse lung protects against lipopolysaccharide induced inflammation. Am J Resp Crit Care Med. Vol 175(8) . 2007:805-815.
- Lin Q, Weis S, Yang G, Weng Y-H, Helston R, Rish K, Smith A, Bordner J, Polte T, Gaunitz F, Dennery PA. Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress. J Biol Chem. Vol 282(28) . 2007:20621-20633.
- Lee H, Pespeni M, Roux J, Dennery PA, Matthay MA, and Pittet JF. HO-1 induction restores c-AMP-dependent lung epithelial fluid transport following severe hemorrhage in rats.. FASEB J. Vol 19(2) . 2005:287-289.
- Dennery PA, Visner G, Weng YH, Nguyen X, Lu F, Zander D, Yang G. Resistance to hyperoxia with HO-1 disruption: role of iron. Free Rad Biol. Vol 34(1) . 2003 Jan:124-133.
- Dennery PA, Lee CS, Ford BS, Weng YH, Yang G, Rodgers PA. Developmental expression of heme oxygenase in the rat lung. Pediatr Res. Vol 53(1) . 2003 Jan:42-47.
- Yang G, Abate A, George A, Weng Y-H, Dennery PA.. Maturational differences in lung NF-kB activation and role in tolerance to hyperoxia.. J Clin Invest. Vol 114. 2004:669-678.