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 i nclude: 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.
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.
|Wright, Clyde J; Sherlock, Laurie G; Sahni, Rakesh et al. (2018) Preventing Continuous Positive Airway Pressure Failure: Evidence-Based and Physiologically Sound Practices from Delivery Room to the Neonatal Intensive Care Unit. Clin Perinatol 45:257-271|
|McKenna, Sarah; Butler, Brittany; Jatana, Laurie et al. (2017) Inhibition of I?B?/NF?B signaling prevents LPS-induced IL1? expression without increasing apoptosis in the developing mouse lung. Pediatr Res 82:1064-1072|
|McKenna, Sarah; Eckman, Molly; Parker, Andrew et al. (2016) Perinatal Endotoxemia Induces Sustained Hepatic COX-2 Expression through an NF?B-Dependent Mechanism. J Innate Immun 8:386-99|
|McKenna, Sarah; Gossling, Megan; Bugarini, Alejandro et al. (2015) Endotoxemia Induces I?B?/NF-?B-Dependent Endothelin-1 Expression in Hepatic Macrophages. J Immunol 195:3866-79|
|McKenna, Sarah; Wright, Clyde J (2015) Inhibiting I?B?-NF?B signaling attenuates the expression of select pro-inflammatory genes. J Cell Sci 128:2143-55|
|Stewart, Michael S; Dietz, Robert M; Landman, Matthew P et al. (2014) Abdominal radiograph with intravesical air and possible small bowel atresia. J Pediatr 164:1238-1238.e1|
|Michaelis, Katherine A; Agboke, Fadeke; Liu, Thanh et al. (2014) I?B?-mediated NF-?B activation confers protection against hyperoxic lung injury. Am J Respir Cell Mol Biol 50:429-38|
|McKenna, Sarah; Michaelis, Katherine A; Agboke, Fadeke et al. (2014) Sustained hyperoxia-induced NF-?B activation improves survival and preserves lung development in neonatal mice. Am J Physiol Lung Cell Mol Physiol 306:L1078-89|
|Tang, Jen-Ruey; Michaelis, Katherine A; Nozik-Grayck, Eva et al. (2013) The NF-?B inhibitory proteins I?B? and I?B? mediate disparate responses to inflammation in fetal pulmonary endothelial cells. J Immunol 190:2913-23|
|Wright, Clyde J; Agboke, Fadeke; Muthu, Manasa et al. (2012) Nuclear factor-?B (NF-?B) inhibitory protein I?B? determines apoptotic cell death following exposure to oxidative stress. J Biol Chem 287:6230-9|
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