Study of White Matter Development in a Rodent Model of Perinatal Brain Injury

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DESCRIPTION (provided by applicant): PROJECT SUMMARY: This is a resubmission of a Mentored Clinical Scientist Research Career Development Award proposal. The proposed training will prepare a young pediatric neurology faculty member for a career as an independent investigator in the field of translational neuroscience research, focusing on perinatal disorders of white matter development. This research will be performed at the Hugo Moser Research Institute at Kennedy Krieger and at the Institute for Cell Engineering and the Department of Neurology at the Johns Hopkins University School of Medicine. This proposal focuses on novel therapies for acquired white matter injuries in neonates, as a paradigm for the acquired, metabolic and genetic disorders of white matter that affect infants and children. This group of disorders is a major cause of brain-based cognitive and motor disabilities. During Dr. Fatemi's medical and clinical training in pediatric neurology, he gained considerable clinical research experience in the fields of neurochemistry, neurogenetics and magnetic resonance imaging; however, he needs additional training in the basic science techniques needed to design cell-based therapies for white matter disorders. The mentored research and didactic experiences outlined in this proposal will build on the candidate's previous clinical and research experiences by using an in vivo mouse model of white matter injury to test the restorative effects of transplantation of glial precursor cells. Dr. Fatemi has developed a novel mouse model of perinatal white matter injury (PWMI) that replicates the salient histopathological and magnetic resonance imaging features observed in human infants with this condition. He has also isolated mouse glial precursor cells, and has demonstrated that these cells survive when implanted in the white matter of mice during the neonatal period. The three specific aims for this proposal have been thoroughly revised, in keeping with the suggestions of the reviewers. Specifically, Aim 1 now involves determining the optimum time of glial precursor cell transplantation that improves cell survival in a mouse model of PWMI. Aim 2 involves modulating the expression of fibroblast growth factor receptors in glial precursors using molecular biological techniques to improve the in vitro and in vivo differentiation of these cells into mature oligogodendrocytes. Aim 3 involves assessing the ability of transplanted glial precursor cells to repair white matter injury and to stimulate the development of new white matter. This 5-year program will include coursework and informal training in animal research, including advanced MRI and histological techniques, as well as cell culture and cell engineering methods. Approximately 80% of the trainee's time will be spent on research, with 20% of his time devoted to clinical activities related to neonatal neurology and the care of older children with white matter disorders. The Kennedy Krieger Institute and the Johns Hopkins University School of Medicine provide an ideal setting for the candidate to establish an independent research career that will ultimately translate basic science advances into novel therapies. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE: Perinatal white matter injury is the most common cause of cerebral palsy in infants born prematurely affecting thousands of babies every year in the United States. There are currently no effective interventions to prevent or repair perinatal white matter injury. This research proposal focuses on the development of novel cell-based therapies in an animal model for this condition and will lay the foundation for future studies with potential clinical implications in children with cerebral palsy.