Selective neuronal vulnerability is an unsolved problem in ischemic pathophysiology. Specific gene products provide early indicators of neuron injury and recovery. Induction of the 70 kDa heat shock / stress protein, hsp72, is directly correlated with the potential for cellular injury, and its timely expression is associated with neuron survival. Establishing the mechanisms and functional significance of this response will identify signalling events determining postischemic neuron damage and/or survival. Functional roles of hsp72 in postischemic injury and recovery will be determined. The requirement for hsp72 in neuronal survival will be tested directly via an in vivo antisense oligonucleotide knockout strategy that will be of general applicability to the question of functional significance of ischemia-induced proteins. Biochemical localization studies will identify proteins and subcellular structures that are targets of hsp72 chaperone function following ischemic stress. An in vitro ischemia model in hippocampal slices will be optimized for the study of changes in gene expression. Routine slices experience ischemia during preparation, inducing c-fos, hsp72 and presumably other ischemia- responsive genes. Methods are proposed to eliminate such triggering events, yielding optimized slices for in vitro anoxia/aglycemia as well as basic physiology studies. Mechanisms of hsp72 induction will be determined in the in vitro ischemia model. Calcium and tyrosine kinases play distinct roles in thermal activation of the heat shock transcription factor, HSF. Pharmacological studies in the slice anoxia/aglycemia model will establish the involvement of these factors in postischemic HSF activation. Subsequent experiments will characterize in detail the signal transduction pathways mediating this response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032344-02
Application #
2270449
Study Section
Neurology A Study Section (NEUA)
Project Start
1994-09-01
Project End
1997-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Neurology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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