Prior studies demonstrate the value of targeted deletion of genes encoding molecules believed to be involved in inflammatory reactions. In the absence of potent and selective antagonists, this approach has been useful for dissecting the role of chemokines, anaphylatoxins and neuropeptides in defined models of injury and disease. In this section of the SCOR application the investigators propose four specific aims to extend these studies.
In Aim 1, they will test the hypothesis that the inflammation and smooth muscle hyperplasia associated with hypoxia and/or hyperoxia results in increased basal and/or allergic airway responsiveness. They will compare reactions of wild type mice and animals with targeted deletion of genes for inflammatory mediators as a mechanistic approach to determine their role in contributing to hypoxic and hyperoxic airway injury.
In Aim 2 they will test the hypothesis that the inflammation and smooth muscle hyperplasia associated with hypoxia and/or hyperoxia alters the animals? ability to clear infections in the lung. Findings will be corroborated by comparison with responses of established gene deleted mouse strains currently under study.
In Aim 3 they will test several additional mouse strains in our established models of airway infection and allergic airway hyperresponsiveness. These strains have been identified in preliminary studies as potentially important for lung development and inflammation by other members of the SCOR. Finally, in Aim 4 the investigators will pursue the observation that deletion of the C3a receptor in the mouse affords protection from the development of allergic airway hyperresponsiveness and that at least some asthmatic humans have elevated levels of C3a in bronchoalveolar lavage fluid following antigen challenge compared with non-asthmatic subjects. The investigators hypothesize that airway hyperresponsiveness is a consequence of activating the C3a/C3a receptor signaling pathway. They propose to analyze this signaling pathway using molecular biological and biochemical techniques. They will additionally extend the human studies by examining C3a levels in tracheal aspirates of preterm infants and correlate findings with clinical outcomes. In achieving these aims, they will gain a better appreciation for the inflammatory components involved in the airway injury associated with newborns and may be able to identify targets for therapy.
| Gregory, Katherine E; Winston, Abigail B; Yamamoto, Hidemi S et al. (2014) Urinary intestinal fatty acid binding protein predicts necrotizing enterocolitis. J Pediatr 164:1486-8 |
| Levesque, Bernadette M; Kalish, Leslie A; Winston, Abigail B et al. (2013) Low urine vascular endothelial growth factor levels are associated with mechanical ventilation, bronchopulmonary dysplasia and retinopathy of prematurity. Neonatology 104:56-64 |
| Van Marter, Linda J; Kuban, Karl C K; Allred, Elizabeth et al. (2011) Does bronchopulmonary dysplasia contribute to the occurrence of cerebral palsy among infants born before 28 weeks of gestation? Arch Dis Child Fetal Neonatal Ed 96:F20-9 |
| Fernandez-Gonzalez, Angeles; Kourembanas, Stella; Wyatt, Todd A et al. (2009) Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype. Am J Respir Cell Mol Biol 40:305-13 |
