This application outlines a career development plan for the applicant who is a practicing neonatologist with an interest in developmental immunology and has the goal of becoming an independent investigator. Under the mentorship of established basic science researchers and a multidisciplinary Advisory Committee, the Principal Investigator will pursue a program of education (coursework, conferences, seminars) and a research project addressing the causation of BPD, a critical issue in neonatal medicine. BPD is a sequence of chronic lung injuries in ventilated premature infants that can be quite severe, resulting in significant morbidity and mortality. Current treatments, including bronchodilator and diuretic therapies, are only palliative. Prevention of BPD using corticosteroids has some benefit, but this has recently been associated with significant and long-term adverse effects. Therefore, it is important to establish methods to identify infants who are at particular risk of developing BPD and to improve preventive therapies. Inflammation and the accumulation of activated neutrophils in the lung play a large part in the pathogenesis of BPD. We hypothesize that reduced clearance of neutrophils from the neonatal lung by apoptosis accounts, in large part, for the severity of inflammatory injuries in BPD, and that this is due to specific alterations in signaling pathways mediating neutrophil activation and apoptosis. To test this hypothesis, blood and lung neutrophil apoptosis in normal and premature infants will be compared with that in adults. Mechanisms underlying reduced apoptosis in neonatal neutrophils will also be analyzed. Quantifying markers for reduced lung neutrophil apoptosis that correlate with the development of BPD may allow us to identify patients at high risk who are good candidates for preventive treatment. The identification of specific pathways mediating apoptosis that are altered in neonatal neutrophils may also suggest preventive therapeutic strategies.
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| Weinberger, Barry; Anwar, Mujahid; Henien, Samir et al. (2004) Association of lipid peroxidation with antenatal betamethasone and oxygen radial disorders in preterm infants. Biol Neonate 85:121-7 |
