Cardiopulmonary arrest remains one of the leading causes of death and disability in the U.S.A. The chances of survival following cardiac arrest are poor, despite fast emergency responses and better techniques of defibrillation. Cardiac arrest with its consequent disruption of blood flow sets in motion a cascade of cellular derangements that result in brain damage, which results from a number of factors, such as free radical formation, release of excitatory amino acids, mitochondrial dysfunction and synaptic dysfunction. Our main hypothesis is that synaptic dysfunction may play a key role in delayed neuronal cell death, and the protein kinase C exerts either positive/negative effects during the post-resuscitative period. The GOAL of proposed research is to define the mechanisms of synaptic dysfunction after cardiac arrest (CA) in the hippocampus. Since this is a broad area, we will emphasize the role of the protein kinase C signal transduction pathway in this pathology.
Specific aims i nclude:
Specific Aim 1 : To define the cellular locus of deltaPKC translocation in the CA1 region of the hippocampus after CA. Our hypothesis is that delta PKC translocates to both pre- and post-synaptic terminals of the CA1 hippocampus and that this triggers synaptic derangements after CA. A second hypothesis is that delta PKC translocation occurs in all three major cell types in the CA1 sub-region of the hippocampus following CA.
Specific Aim 2 : To define the intracellular locus of the delta PKC translocation in the CA1 sub-region of the hippocampus after CA.
This aim will define the intracellular locus of delta PKC translocation following CA.
Specific Aim 3 : To define the delta PKC effect on synaptic physiology after CA. Under this aim, we will tackle one of the specific sites that we hypothesize is involved in CA induced damage, the synaptic terminal. Our hypothesis is that the delta PKC isozyme alters synaptic activity in such a way that it promotes synaptic dysfunction after CA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045676-03
Application #
7074702
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hicks, Ramona R
Project Start
2004-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$342,111
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
052780918
City
Miami
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
Xu, Jing; Jackson, Charlie W; Khoury, Nathalie et al. (2018) Brain SIRT1 Mediates Metabolic Homeostasis and Neuroprotection. Front Endocrinol (Lausanne) 9:702
Stradecki-Cohan, Holly M; Youbi, Mehdi; Cohan, Charles H et al. (2017) Physical Exercise Improves Cognitive Outcomes in 2 Models of Transient Cerebral Ischemia. Stroke 48:2306-2309
Koronowski, Kevin B; Khoury, Nathalie; Saul, Isabel et al. (2017) Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance. Stroke 48:3117-3125
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
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
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

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