Enhanced EGF Receptor Signaling Prevents White Matter Injury in Perinatal Hypoxia

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DESCRIPTION (provided by applicant): This Mentored Clinical Scientist Research Career Development Award will prepare a child neurology faculty member for an academic career as an independent investigator in multidisciplinary translational neuroscience research with a focus on white matter injury and recovery after premature brain injury. This research will be conducted in the Center for Neuroscience at Children's National Medical Center. Diffuse periventricular white matter injury (DWMI) is a major form of brain injury in children born very premature and results in long-term cognitive, sensori-motor and behavioral deficiencies. There are currently no specific targeted therapies that promote white matter recovery. This proposal focuses on the Epidermal Growth Factor Receptors (EGFR) found on endogenous progenitor cells in the brain and whether enhancing their signaling with specific targeted therapies promote recovery of white matter oligodendrocytes. Dr Scafidi is a child neurologist with a primary focus on neonatal neurology and the long-term care and management of these children. During Dr Scafidi's training as a child neurologist, he gained experience in the fields of developmental neurobiology, clinical neurophysiology and neuroimaging. However, Dr Scafidi needs additional training in basic neuroscience techniques to investigate whether specific targeted therapies that enhance endogenous EGFR signaling promotes recovery using a multidisciplinary approach that involves cellular, molecular, metabolic and physiology techniques as well as behavioral studies. Dr Scafidi is using a novel mouse model of chronic perinatal hypoxia that results in neuropathological and neurobehavioral changes similar to those found in human very preterm infants. The proposed aims of this study will address the overall hypothesis that enhanced EGFR signaling stimulates the endogenous response of EGFR+ progenitor cells during a critical period in brain development after injury and promotes cellular, functional and behavioral recovery after hypoxia. In aim 1, Dr Scafidi will determine the role of EGF on oligodendrocyte regeneration and developmental myelination after chronic perinatal hypoxia. In Aim 2, he will determine the functional deficits caused by chronic perinatal hypoxia on axon integrity and whether over-expression of EGFR in oligodendrocytes or treatment with EGFR ligand promotes functional recovery. Finally, in the third aim Dr Scafidi will define the long-term behavioral deficits induced by chronic perinatal hypoxia and determine whether enhanced EGFR signaling prevents these deficits. This 5-year program will include didactic and research training from an excellent team of mentors and advisors. 75% of Dr Scafidi's time will be devoted to research, with the remaining time devoted to the clinical activities related to neonatal neurology and long-term care of those born prematurely. The Center for Neuroscience Research under the direction of his primary mentor is the ideal setting for a candidate to develop into an independent investigator in a multidisciplinary and collaborative environment.