The role of chorioamnionitis-induced perinatal alterations of Heme-oxygenase-1 (HO-1) pathway on neuroinflammation and neonatal white matter injury

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PROJECT SUMMARY/ABSTRACT: The proposal in this application outlines a five-year training program for the development of a career as a physician-scientist in neonatal neuroimmunology. Candidate, Dr. Maide Ozen, is an Early Stage Investigator and an Assistant Professor of Pediatrics at the Johns Hopkins University School of Medicine. The proposed research will be carried out under the primary mentorship of Dr. Lauren L. Jantzie, PhD, an expert leader in translational investigations in perinatal brain injury. Candidate’ s co-mentors are Dr. Shenandoah Robinson, M.D. an expert in oligodendrocyte biology and Dr. Frances J. Northington, M.D. an esteemed Neonatologist and a leader in cell death pathways in the brain. Specific training objectives of this K08 proposal are: develop Dr. Ozen’s scientific and professional skills in 1) advanced neuroimmunology and neuroscience techniques, 2) gene-protein interactions specific to Heme oxygenase-1 (HO-1) to lay the foundation for a future R01 application. Neuroscience research at JHU is exceptionally strong. Dr. Ozen and her mentoring committee have developed a focused approach to achieve these objectives. The experiential research environment, intellectual guidance and carefully selected didactic courses, each matched to a specific aim in this proposal, will ensure rigorous training in neuroimmunology for achieving independence. White matter injury (WMI) is the most common form of brain injury in preterm neonates. Key focus of candidates proposed project is interrogating HO-1 pathway, for the first time, in perinatal WMI. HO-1 is an anti- inflammatory, anti-apoptotic and cytoprotective enzyme with essential roles in immune regulation and is expressed in mononuclear cells, microglia and oligodendrocytes. The candidate is the first to show that chorioamnionitis-induced perinatal alterations of HO-1 pathway in the developing rat brain correlate with neuroinflammation. Therefore, utilizing a validated CHORIO model of Cerebral Palsy, the candidate will first determine how CHORIO alters HO-1 pathway in WMI; second, determine if intracellular HO-1 expression in peripheral mononuclear cells and brain microglia differentially contribute to WMI in CHORIO; third, determine if modulation of HO-1 pathway will protect from WMI in CHORIO. Completion of the targeted career development program and research proposed in this proposal will allow the candidate to learn new technical skills and gain neuroscience expertise to excel as a physician-scientist in neuroimmunology and advance the field of HO-1 biology to perinatal brain injury. Rigorous inquiry in regulation of HO-1 pathway in CHORIO could provide discovery of novel biomarkers and targeted therapeutic strategies for perinatal immune-mediated WMI.