The unique role of IkBa in modulating NF-kB activity in the newborn lung.
Principal Investigator: CLYDE JASON WRIGHT
Abstract: DESCRIPTION (provided by applicant): This proposal describes the 5-year training program for the development of an academic career in molecular biology and Neonatology. The candidate is in his final year of the Pediatric Scientist Development Program and Neonatology fellowship at the Children's Hospital of Philadelphia (CHOP). This program will expand a body of work in the molecular biology of hyperoxic neonatal lung injury. Phyllis Dennery, MD, a recognized leader in the field of neonatal pulmonary gene regulation in oxidative stress and Professor of Pediatrics at CHOP and the University of Pennsylvania, will supervise the training program. The program will be co-mentored by Michael Beers, MD, an established authority on lung injury and Professor of Medicine at the University of Pennsylvania. To enhance training, an advisory committee consisting of distinguished scientists with expertise in academic medicine, lung injury and NF-kB signaling has been enlisted to provide advice and guidance. Faculty professional development seminars and didactic courses will enhance the educational content of the program. The Division of Neonatology and Department of Pediatrics of CHOP and University of Pennsylvania provide a unique combination of resources, core facilities, intellectual expertise and potential collaborations to support young faculty. This is an ideal training environment to transition to an independent academic career as a physician-scientist. In preterm infants, bronchopulmonary dysplasia (BPD) is common and leads to significant long-term morbidity. Clinical studies have correlated NF-kB activation to an increased risk of developing BPD. Hyperoxia induces NF-kB activation in the neonatal mouse lung. However, the mechanistic pathway leading to this activation and downstream effects are unknown. The central hypothesis of this proposal is that IkB1, a NF-kB inhibitory protein, has unique characteristics that make it essential for regulating hyperoxia-induced NF-kB activation in the newborn lung. The specific aims include: 1) Defining the developmental expression profile of IkB1 in the fetal and neonatal mouse lung, 2) Testing the role of the IkB1 specific atypical pathway of NF-kB activation in modulating lung injury in neonatal mice exposed to hyperoxia, and 3) Determining whether nitric oxide inhibits the atypical pathway of NF-KB activation. By further defining the unique characteristics of IkB1 and its role in modulating hyperoxia-induced NF-kB activation, we hope to identify interventions targeted at protecting preterm infants from BPD. PUBLIC HEALTH RELEVANCE: Project Narrative Preterm delivery affects more than 12% of all births and accounts for more than 85% of all perinatal complications. Premature delivery predisposes infants to the development of bronchopulmonary dysplasia, or chronic lung disease, and each year 10,000 to 15,000 newborns develop this disease. Interventions aimed at preventing the development of BPD will reduce the impact of this major public health burden.
Funding Period: 2010-04-01 - 2015-03-31
more information: NIH RePORT
- NO inhibits hyperoxia-induced NF-κB activation in neonatal pulmonary microvascular endothelial cellsClyde J Wright
Department of Pediatrics, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
Pediatr Res 68:484-9. 2010..This may help to explain the protective effects of NO on hyperoxic injury in the developing lung vasculature...
- Nuclear factor-κB (NF-κB) inhibitory protein IκBβ determines apoptotic cell death following exposure to oxidative stressClyde J Wright
Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA
J Biol Chem 287:6230-9. 2012..These findings represent a necessary but not sufficient role of IκBβ in preventing oxidant stress-induced cell death...
- The NF-κB inhibitory proteins IκBα and IκBβ mediate disparate responses to inflammation in fetal pulmonary endothelial cellsJen Ruey Tang
Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO 80045, USA
J Immunol 190:2913-23. 2013....
- IκBβ-mediated NF-κB activation confers protection against hyperoxic lung injuryKatherine A Michaelis
1 Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
Am J Respir Cell Mol Biol 50:429-38. 2014..We conclude that sustained NF-κB activity mediated by IκBβ protects against hyperoxic lung injury through increased expression of antiapoptotic genes. ..
- Oxidative stress and inflammation modulate Rev-erbα signaling in the neonatal lung and affect circadian rhythmicityGuang Yang
1 Division of Neonatology, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania
Antioxid Redox Signal 21:17-32. 2014..Nevertheless, it is not known whether circadian genes are regulated by these stimuli. We evaluated whether Rev-erbα, a key circadian gene, was regulated by oxidative stress and/or inflammation in vitro and in a mouse model...