Ischemic preconditioning (PC) is a phenomenon whereby various stimuli, which themselves do not cause neuronal injury, will significantly reduce the vulnerability of the brain to subsequent lethal ischemia. Ischemic tolerance conferred by a PC stimulus appears to require new gene transcription and protein synthesis. Multiple intracellular pathways have been identified that initiate the PC response, but the genes ultimately responsible remain elusive. Microarray analysis permits the rapid identification and semi-quantification of a large number of genes, making it ideal for studying complex mechanisms such as PC. The hypothesis of the proposed work is that microarray analysis will permit the identification of genes upregulated or downregulated by the PC stimuli and ultimately confer ischemic tolerance. Because many genes are modulated following a noxious stimulus, most of which are not involved in PC, the challenge is to separate relevant genes from those that are mere epiphenomena. Pharmacologic blockade of the PC cascade during application of the PC stimulus can help filter relevant from epiphenomena genes. The following are the specific aims of the proposed work: 1) To identify the genes whose transcription is modulated by sublethal ischemia and separate genes relevant to PC from those that are epiphenomena by the use of pharmacologic inhibitors of PC; 2) To identify the genes whose transcription is modulated following a lethal ischemic insult in preconditioned versus non-preconditioned animals; 3) To create a pool of gene candidates with potential involvement in mediating PC; 4) To determine the PC candidate genes and to confirm their modulation by rt-PCR, immunohistochemistry, and Western blotting; 5) To confirm the relevance of the identified genes to PC by pharmacologically modulating the genes in vivo and then to determine the effect of this modulation on neuronal outcome. The ultimate goal of the proposed research is to identify neuroprotective programs endogenous to neurons and to evoke these programs in patients who are at risk for cerebral ischemia. A substantial benefit of the research will be the identification of novel therapeutic targets upon which future drug development can be based.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047570-04
Application #
7210575
Study Section
Special Emphasis Panel (ZRG1-SSS-8 (02))
Program Officer
Golanov, Eugene V
Project Start
2004-06-01
Project End
2008-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$356,093
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Panneerselvam, Mathivadhani; Patel, Piyush M; Roth, David M et al. (2011) Role of decoy molecules in neuronal ischemic preconditioning. Life Sci 88:670-4
Head, Brian P; Patel, Hemal H; Niesman, Ingrid R et al. (2009) Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology 110:813-25
Patel, Piyush; Sun, Lena (2009) Update on neonatal anesthetic neurotoxicity: insight into molecular mechanisms and relevance to humans. Anesthesiology 110:703-8
Head, Brian P; Patel, Hemal H; Tsutsumi, Yasuo M et al. (2008) Caveolin-1 expression is essential for N-methyl-D-aspartate receptor-mediated Src and extracellular signal-regulated kinase 1/2 activation and protection of primary neurons from ischemic cell death. FASEB J 22:828-40
Feng, Zheng; Davis, Daniel P; Sasik, Roman et al. (2007) Pathway and gene ontology based analysis of gene expression in a rat model of cerebral ischemic tolerance. Brain Res 1177:103-23
Patel, Hemal H; Tsutsumi, Yasuo M; Head, Brian P et al. (2007) Mechanisms of cardiac protection from ischemia/reperfusion injury: a role for caveolae and caveolin-1. FASEB J 21:1565-74