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.
Preterm birth is a major public health concern due to significant neurodevelopmental delays that result and attributed to white matter injury in the brain. There are no therapies available that promote recovery and repair. The goal of this project is to promote cellular, metabolic, physiologic and behavior recovery of white matter injury sequelae by enhancing specific signaling pathways of endogenous progenitor cells in the brain.
|Scafidi, Joseph; Ritter, Jonathan; Talbot, Brooke M et al. (2018) Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible. Cancer Res 78:2081-2095|
|Zonouzi, Marzieh; Scafidi, Joseph; Li, Peijun et al. (2015) GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury. Nat Neurosci 18:674-82|
|Yadavilli, Sridevi; Scafidi, Joseph; Becher, Oren J et al. (2015) The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma. Oncotarget 6:12141-55|
|Agematsu, Kota; Korotcova, Ludmila; Scafidi, Joseph et al. (2014) Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model. Pediatr Res 75:618-25|
|Salmaso, Natalina; Jablonska, Beata; Scafidi, Joseph et al. (2014) Neurobiology of premature brain injury. Nat Neurosci 17:341-6|
|Scafidi, Joseph; Hammond, Timothy R; Scafidi, Susanna et al. (2014) Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature 506:230-4|
|Coleman, Maya B; Glass, Penny; Brown, Judy et al. (2013) Neonatal neurobehavioral abnormalities and MRI brain injury in encephalopathic newborns treated with hypothermia. Early Hum Dev 89:733-7|
|Mangin, Jean-Marie; Li, Peijun; Scafidi, Joseph et al. (2012) Experience-dependent regulation of NG2 progenitors in the developing barrel cortex. Nat Neurosci 15:1192-4|
|Ishibashi, Nobuyuki; Scafidi, Joseph; Murata, Akira et al. (2012) White matter protection in congenital heart surgery. Circulation 125:859-71|
|Jablonska, Beata; Scafidi, Joseph; Aguirre, Adan et al. (2012) Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression. J Neurosci 32:14775-93|
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