Cardiac arrest (CA) and stroke remain two of the leading causes of death and disability in the U.S.A. In particular, CA with its consequent disruption of blood flow sets in motion a cascade of cellular derangements that result in selective brain damage and delayed cell death. It has been postulated that delayed cell death after brain ischemia may result from two different mechanisms: apoptosis and/or necrosis. In both pathways however, mitochondrial dysfunction appears to play a pivotal role. However, the precise mechanisms of how mitochondrial dysfunction occurs following cerebral ischemia have not been fully elucidated. Although different signaling pathways are expected to play a role in mitochondrial dysfunction, our main hypothesis is that an aberrant signal transduction pathway involving protein kinase C delta (dPKC), underlies mitochondrial dysfunction (Figure 1). In contrast to the negative role of dPKC, we have recently demonstrated that ePKC plays a pivotal role in the induction of tolerance after ischemic preconditioning (IPC). In contrast to the pro-apoptotic role of dPKC, cleavage of ePKC by caspase-7 results in the activation of ePKC, which was associated with its anti-apoptotic function in MCF-7 cells. Cleavage of ePKC has never been reported in the CNS. Also, formation of mitochondrial ePKC-ERK 1/2 modules was coupled to the inactivation of Bad, a pro-apoptotic molecule. Since ischemic preconditioning has been shown to preserve mitochondrial function, we conjecture that ePKC promotes ischemic tolerance by protecting mitochondrial function. We propose in this application to determine the mechanisms by which ePKC protects neuronal mitochondria whereas dPKC promotes cell death after cerebral ischemia. To this end, we propose the following aims: 1) Determine the mechanisms and time course that promote translocation/activation of either ePKC or dPKC in neurons after IPC/ischemia or pharmacological stimuli and whether these isozymes translocate to mitochondria;2) To determine the mechanisms by which dPKC translocation/cleavage promote mitochondrial dysfunction and their role in neuronal death after cerebral ischemia;and 3) To determine the mechanisms by which ePKC translocation/cleavage promote mitochondrial protection after cerebral ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054147-04
Application #
7619264
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Bosetti, Francesca
Project Start
2006-07-06
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$334,267
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Narayanan, Srinivasan V; Dave, Kunjan R; Perez-Pinzon, Miguel A (2018) Ischemic Preconditioning Protects Astrocytes against Oxygen Glucose Deprivation Via the Nuclear Erythroid 2-Related Factor 2 Pathway. Transl Stroke Res 9:99-109
Morris-Blanco, Kahlilia C; Dave, Kunjan R; Saul, Isabel et al. (2016) Protein Kinase C Epsilon Promotes Cerebral Ischemic Tolerance Via Modulation of Mitochondrial Sirt5. Sci Rep 6:29790
Koronowski, Kevin B; Dave, Kunjan R; Saul, Isabel et al. (2015) Resveratrol Preconditioning Induces a Novel Extended Window of Ischemic Tolerance in the Mouse Brain. Stroke 46:2293-8
Cohan, Charles H; Neumann, Jake T; Dave, Kunjan R et al. (2015) Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats. PLoS One 10:e0124918
Narayanan, Srinivasan V; Dave, Kunjan R; Saul, Isa et al. (2015) Resveratrol Preconditioning Protects Against Cerebral Ischemic Injury via Nuclear Erythroid 2-Related Factor 2. Stroke 46:1626-32
Neumann, Jake T; Thompson, John W; Raval, Ami P et al. (2015) Increased BDNF protein expression after ischemic or PKC epsilon preconditioning promotes electrophysiologic changes that lead to neuroprotection. J Cereb Blood Flow Metab 35:121-30
Koronowski, Kevin B; Perez-Pinzon, Miguel A (2015) Sirt1 in cerebral ischemia. Brain Circ 1:69-78
Thompson, John W; Narayanan, Srinivasan V; Koronowski, Kevin B et al. (2015) Signaling pathways leading to ischemic mitochondrial neuroprotection. J Bioenerg Biomembr 47:101-10
Morris-Blanco, Kahlilia C; Cohan, Charles H; Neumann, Jake T et al. (2014) Protein kinase C epsilon regulates mitochondrial pools of Nampt and NAD following resveratrol and ischemic preconditioning in the rat cortex. J Cereb Blood Flow Metab 34:1024-32
Lin, Hung Wen; Gresia, Victoria L; Stradecki, Holly M et al. (2014) Protein kinase C delta modulates endothelial nitric oxide synthase after cardiac arrest. J Cereb Blood Flow Metab 34:613-20

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