(PI's abstract) This application is submitted in response to PAS 99-080, """"""""Exploratory Grants in Pediatric Brain Disorders: Integrating the Science."""""""" The proposal will lay the foundation for a new inter-institutional collaboration (Univ. Of Michigan and Wayne State Univ.) between clinician scientists with expertise in the pathogenesis of brain injury (Drs. Silverstein and Barks), and a neuroanatomist with expertise in oligodendroglial development (Dr. Skoff). The long-term goal of the proposed research is to develop novel approaches for understanding the pathogenesis of hypoxic-ischemic white matter injury in the immature brain. Studies of neonatal ischemic brain injury in experimental models have focused on mechanisms of neuronal injury and neuroprotection, and have largely neglected white matter injury. Yet, in human neonates and young infants the white matter, particularly in periventricular regions, is highly susceptible tp ischemic injury. In preliminary experiments, in situ hybridization and RT-PCR assays were developed to examine injury-induced changes in expression of 2 oligodendroglia (OL)-specific genes, proteolipid protein (PLP), and myelin basic protein (MBP); preliminary findings provide the impetus for this application. Experiments performed in immature rodent stroke models (in neonatal rats and mice) revealed that hypoxic ischemic injury results in acute disruption of OL gene expression within periventricular white matter; and also alters expression of OL-specific genes in cells in the sub-ventricular zone; in neonatal rats, intraventricular injection of the excitatory amino acid agonist AMPA results in a similar pattern of acute disruption of OL gene expression. This application proposes to build upon these finding to develop novel approaches for understanding mechanisms of OL injury in the immature brain.
Aim 1 will: evaluate the influence of hypoxia-ischemia (HI) on PLP and MBP gene expression; determine whether acute HI induced suppression of OL-gene expression predicts the severity of chronic OL damage; and evaluate the impact of specific interventions that could exacerbate or attenuate HI-induced OL injury.
Aim 2 will examine the influence of AMPA lesioning on PLP and MBP gene expression and OL injury.
Aim 3 focuses upon the impact of HI on OL precursors in the ventricular and subventricular zones; and specifically will analyze whether these OL precursors undergo apoptosis, whether the loss of OL precursors is permanent, and whether mild HI insults can elicit a proliferative response in these cells. Taken together, results of these experiments will improve our understanding of the impact of HI on OL in the immature brain and enhance development of more effective therapeutic approaches to limit or prevent neonatal ischemic white matter injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS040824-01
Application #
6230600
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Spinella, Giovanna M
Project Start
2001-04-15
Project End
2004-03-31
Budget Start
2001-04-15
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$192,741
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Skoff, Robert P; Bessert, Denise; Barks, John D E et al. (2007) Plasticity of neurons and glia following neonatal hypoxic-ischemic brain injury in rats. Neurochem Res 32:331-42
Xu, G; Ong, J; Liu, Y-Q et al. (2005) Subventricular zone proliferation after alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated neonatal brain injury. Dev Neurosci 27:228-34
Ong, Jennifer; Plane, Jennifer M; Parent, Jack M et al. (2005) Hypoxic-ischemic injury stimulates subventricular zone proliferation and neurogenesis in the neonatal rat. Pediatr Res 58:600-6
Zaidi, Aliya U; Bessert, Denise A; Ong, Jennifer E et al. (2004) New oligodendrocytes are generated after neonatal hypoxic-ischemic brain injury in rodents. Glia 46:380-90
Plane, Jennifer M; Liu, Ruowen; Wang, Tsu-Wei et al. (2004) Neonatal hypoxic-ischemic injury increases forebrain subventricular zone neurogenesis in the mouse. Neurobiol Dis 16:585-95