Our long-term objective is to establish the role of poly(ADP-ribose) polymerase-1 (PARP-1) in the pathogenesis of allergen-induced respiratory diseases such as asthma and to develop a treatment strategy based on the inhibition of this enzyme for asthma. Airway inflammation is a central feature of the pathogenesis of asthma. Reactive oxygen (ROS) and nitrogen (RNS) species contribute to inflammation by damaging DNA, which, in turn, results in the activation of PARP-1. The depletion both of the substrate of this enzyme (NAD) and of the NAD precursor ATP as a result of persistent activation of PARP-1 leads to a cellular energy crisis and, eventually, to cell death. We propose to test the hypothesis that ROS and RNS generated during allergen exposure induce DNA damage and persistent activation of PARP-1 in airway epithelial cells, resulting in the depletion of cellular energy reserves and airway inflammation. For the proposed studies, we intend to use the well-established mouse model of allergen (ovalbumin)-triggered lung inflammation. Our preliminary data show that PARP-1 is activated in lungs of ovalbumin-challenged mice may exacerbate the inflammatory response by promoting the expression of the inducible nitric oxide synthase (iNOS), in part, through its promotion of the activation of the pro-inflammatory transcription factor, NF-kappaB. Inhibition of PARP-1, either pharmacologically or by gene knockout, results in a marked decrease in the extent of inflammation in the lungs of ovalbumin-challenged mice and almost a complete inhibition of iNOS expression. We therefore plan (1) to demonstrate further and to characterize the role of PARP-1-mediated depletion of NAD and ATP in the pathogenesis of allergen-induced lung inflammation. (2) We will investigate the mechanism by which PARP-1 is activated in lungs of ovalbumin-exposed mice and establish the relation between iNOS expression, RNS generation, and PARP-1 activation in allergen-induced lung inflammation. (3) Finally, with the use of the animal model and primary lung epithelial cells, we will examine the mechanism by which PARP-1 promotes the activation of NF-?B during allergen-induced lung inflammation. We will establish the connection between PARP-1 activation, ROS/RNS generation, and NF-kappaB activation. The results of the proposed study should provide insight into the suitability of PARP-1 as a novel target for the treatment of allergen-induced respiratory diseases such as asthma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Biology and Pathology Study Section (LBPA)
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Noel, Patricia
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Louisiana State University Hsc New Orleans
Schools of Medicine
New Orleans
United States
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Ghonim, Mohamed A; Wang, Jeffrey; Ibba, Salome V et al. (2018) Sulfated non-anticoagulant heparin blocks Th2-induced asthma by modulating the IL-4/signal transducer and activator of transcription 6/Janus kinase 1 pathway. J Transl Med 16:243
Al-Khami, A A; Ghonim, M A; Del Valle, L et al. (2017) Fuelling the mechanisms of asthma: Increased fatty acid oxidation in inflammatory immune cells may represent a novel therapeutic target. Clin Exp Allergy 47:1170-1184
Ibba, Salome' V; Ghonim, Mohamed A; Pyakurel, Kusma et al. (2016) Potential of Inducible Nitric Oxide Synthase as a Therapeutic Target for Allergen-Induced Airway Hyperresponsiveness: A Critical Connection to Nitric Oxide Levels and PARP Activity. Mediators Inflamm 2016:1984703
Lammi, Matthew R; Ghonim, Mohamed A; Pyakurel, Kusma et al. (2016) Treatment with intranasal iloprost reduces disease manifestations in a murine model of previously established COPD. Am J Physiol Lung Cell Mol Physiol 310:L630-8
El-Bahrawy, Ali; Tarhuni, Abdelmetalab; Kim, Hogyoung et al. (2016) ApoE deficiency promotes colon inflammation and enhances inflammatory potential oxidized-LDL and TNF-? in colon epithelial cells. Biosci Rep :
Ghonim, Mohamed A; Pyakurel, Kusma; Ibba, Salome V et al. (2015) PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice. Clin Sci (Lond) 129:951-62
Ghonim, Mohamed A; Pyakurel, Kusma; Ibba, Salome V et al. (2015) PARP inhibition by olaparib or gene knockout blocks asthma-like manifestation in mice by modulating CD4(+) T cell function. J Transl Med 13:225
Kim, Hogyoung; Tarhuni, Abdelmetalab; Abd Elmageed, Zakaria Y et al. (2015) Poly(ADP-ribose) polymerase as a novel regulator of 17?-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis. J Transl Med 13:233
Ghonim, Mohamed A; Pyakurel, Kusma; Ju, Jihang et al. (2015) DNA-dependent protein kinase inhibition blocks asthma in mice and modulates human endothelial and CD4? T-cell function without causing severe combined immunodeficiency. J Allergy Clin Immunol 135:425-40
Tsumagari, Koji; Abd Elmageed, Zakaria Y; Sholl, Andrew B et al. (2015) Simultaneous suppression of the MAP kinase and NF-?B pathways provides a robust therapeutic potential for thyroid cancer. Cancer Lett 368:46-53

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