Cerebral ischemia as a result of strokes or cardiac arrest remains one of the leading causes of death and disability in the U.S.A. It is now well accepted that mitochondria are key players in cerebral ischemic/reperfusion injury hours to days following the ischemic insult. The main goals were the elucidation of signaling pathways involved in the fate of brain mitochondria following cerebral ischemia. Studies from us and other groups, have demonstrated Protein Kinase C isozyme (PKC?) translocates to mitochondria to activate pathways of neuroprotection. We have identified that PKC? acts as a signaling metabolic master regulator that alters NAD levels, mitochondrial sirtuins and cell metabolism and promotes neuroprotection against cerebral ischemia. Previous studies demonstrated the importance of NAD replenishment in neuroprotection against cerebral ischemia. Thus, we propose experiments to elucidate the mechanisms by which PKC? alters NAD levels in the brain and define its downstream pathways that enhance ischemic tolerance. These goals will be achieved in the following specific aims: 1) To determine if PKC? via Sirt1 promotes increases of the NAD+ biosynthetic pathway and define the role of this pathway in ischemic neuroprotection. Model: Mouse; Paradigm: Oxygen-Glucose Deprivation (OGD); 2) To determine if the PKC?/Sirt1 pathway promotes a `caloric restriction' (CR)-like bioenergetic phenotype in the brain. Model: Mouse; Paradigm: Oxygen-Glucose Deprivation (OGD), Middle Cerebral Artery Occlusion (MCAo); and 3) To determine whether post-treatment with a PKC? activator can rescue the NAD+ salvage pathway and its downstream pathways following MCAo in aged rats. Model: Rat; Paradigm: MCAo.

Public Health Relevance

Cerebral ischemia in the form of stroke or cardiopulmonary arrest remains one of the leading causes of death and disability in the USA. A major pathological consequence of cerebral ischemia is reperfusion injury and oxidative damage. This proposal examines the molecular mechanisms by which brain bioenergetics is impaired following cerebral ischemia. The goal is to find novel therapeutic agents that may benefit patients that undergo strokes or acute myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS097658-04
Application #
9904768
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2017-08-15
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
4
Fiscal Year
2020
Total Cost
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
Koronowski, Kevin B; Khoury, Nathalie; Morris-Blanco, Kahlilia C et al. (2018) Metabolomics Based Identification of SIRT5 and Protein Kinase C Epsilon Regulated Pathways in Brain. Front Neurosci 12:32
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
Khoury, Nathalie; Koronowski, Kevin B; Young, Juan I et al. (2018) The NAD+-Dependent Family of Sirtuins in Cerebral Ischemia and Preconditioning. Antioxid Redox Signal 28:691-710
Xu, Jing; Jackson, Charlie W; Khoury, Nathalie et al. (2018) Brain SIRT1 Mediates Metabolic Homeostasis and Neuroprotection. Front Endocrinol (Lausanne) 9:702
Jackson, Charles W; Escobar, Iris; Xu, Jing et al. (2018) Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5' adenosine monophosphate-activated protein kinase and sirtuins. Brain Circ 4:54-61
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
Narayanan, Srinivasan V; Perez-Pinzon, Miguel A (2017) Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Cond Med 1:2-8