The purpose of this project is to elucidate the cellular and molecular events which promote recovery following cerebral hypoxia-ischemia in the immature rat. The overall hypothesis is that specific cellular and molecular mechanisms are induced in the brain in response Preliminary studies from our laboratory demonstrate that two such in vivo paradigms which can be studied in the 7-old rat are: 1) short-intermediate intervals of hypoxia-ischemia. The experimented proposed in this research project are designed to investigate three major, interrelated areas of functional activity in the immature brain which may promote cellular survival after hypoxia-ischemia: cerebral nutrient transport, neuroprotective actions of growth factors, and the role of astrocytes in maintaining homeostasis and promoting neuronal survival. To this end, this project will pursue three specific aims: 1) to determine the effect the effect of the duration and severity of the hypoxic-ischemia insult on the nature and time-course of alterations in neural gene and protein expression and the relationship of these changes to tissue damage. These studies will employ in situ hybridization and protein analyses to assess alterations in glucose and monocarboxylate transporter proteins and the neurotrophins, in combination with MR imaging and detailed neuropathological analysis to recreate the temporal and spatial pattern of cellular changes following mild-moderate, relative to severe, ischemia; 2) to determine the mechanisms by which hypoxic preconditioning protects against known to provide significant approach as in Aim 1 in a experimental paradigm of hypoxic preconditioning known to provide significant neuroprotection from a subsequent severe ischemic insult: and 3) to determine the role of astrocytes which became activity within the hypoxic ischemic-hemisphere early in recovery in providing neuroprotection. The experiments will combined combine two in vivo and in vitro approaches to investigate the functional activity of activated astrocytes which may contribute to neuronal survival. The results of these studies will provide important information relative to the cellular and molecular basis of the pathophysiology of hypoxic-ischemic brain damage in the immature animal in conditions commensurate with tissue survival.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD030704-08
Application #
6484764
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2001-07-01
Project End
2002-06-30
Budget Start
Budget End
Support Year
8
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Sen, Ellora; Basu, Anirban; Willing, Lisa B et al. (2011) Pre-conditioning induces the precocious differentiation of neonatal astrocytes to enhance their neuroprotective properties. ASN Neuro 3:e00062
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Nehlig, Astrid; Rudolf, Gabrielle; Leroy, Claire et al. (2006) Pentylenetetrazol-induced status epilepticus up-regulates the expression of glucose transporter mRNAs but not proteins in the immature rat brain. Brain Res 1082:32-42
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Basu, Anirban; Lazovic, Jelena; Krady, J Kyle et al. (2005) Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury. J Cereb Blood Flow Metab 25:17-29

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