The mechanism of neuronal injury and death in brain ischemia has been further defined over the past decade and the important differences in the pathogenesis of focal versus global ischemia clarified. Based on these discoveries the clinical and experimental treatment of stroke now employs a number of pharmacological strategies including inhibition of the deleterious effects of excitatory amino acids and intracellular Ca++ accumulation. The new knowledge that acute excitatory neurotransmitter-induced changes in focal brain ischemia are associated with alterations in gene expression offers a new opportunity for novel therapy. The hypothesis of this study is that some of the new gene products expressed after ischemia promote neuronal survival and decrease susceptibility to subsequent ischemia. Based on our preliminary data and previous studies, we propose to study members of the following gene families: 1) antiapoptotic genes (including bcl-2, bcl-x-long, bcl-x- beta), 2) stress proteins (including hsp 70, grp75, grp78), and 3) the GADD family of DNA damaged related genes.
Specific aims are: 1) Determine which of the above-named mRNAs and proteins are expressed in ischemic regions that survive transient focal occlusion of the middle cerebral artery (MCA) of a duration adequate to induce ischemia, without infarction. 2) Compare the pattern of expression in aim 1 with mRNA and protein expression in regions that die following transient focal occlusion of the MCA of a duration adequate to induce ischemia with infraction. 3) Determine which genes are expressed in regions of brain after preconditioning with sublethal focal ischemia sufficient to produce tolerance to subsequent lethal focal ischemia. Determine if these genes are expressed at times when tolerance is present. Genes that are expressed in regions that survive after focal ischemia (aim 1) and in tolerant brain (aim 3) but not in dying neurons (aim 2) will be considered candidate endogenous neuroprotectants. 4) Test the neuroprotective role of genes identified as above by inhibiting the translation of the candidate gene's protein using antisense oligodeoxynucleotides in vivo and by measuring the resulting changes in infarct size and selective neuronal loss. Further, determine if antisense oligonucleotide treatment alters induction of tolerance after brief focal ischemia. 5) Identify novel genes induced i ischemic brain by subtractive hybridization. Understanding the role of both known and novel gene induction in ischemia may lead to new strategies for the treatment of stroke as well as other neurodegenerative diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology A Study Section (NEUA)
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Jacobs, Tom P
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Emanuel Hospital and Health Center
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Thompson, Simon; Pearson, Andrea N; Ashley, Michelle D et al. (2011) Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection. J Biol Chem 286:19331-9
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Thompson, Simon J; Loftus, Liam T; Ashley, Michelle D et al. (2008) Ubiquitin-proteasome system as a modulator of cell fate. Curr Opin Pharmacol 8:90-5

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