The long-term goal of this translational research program is to develop an in-depth understanding of the events that protect neurons from stroke in order to improve neuroprotective therapies. Stroke is the third leading killer in the U.S. yet there is a paucity of interventions available to provide neuroprotection. However, powerful endogenous pathways exist to control CNS cell death. These pathways are exploited in a phenomenon known as ischemic preconditioning in which neurons exposed to a sublethal challenge are subsequently provided profound resistance. The pathways recruited during preconditioning could provide novel and potent defensive targets. The ability to regulate molecular constituents requires an in-depth understanding of the signaling systems that contribute to this protective pathway. We have previously determined that elements traditionally associated with cell death, such as production of reactive oxygen species, are required for preconditioning. Recent advances in our understanding of stress-induced signaling suggests that there may be a previously under-appreciated conserved pathway which underlies preconditioning. We have developed a powerful, accessible and reproducible paradigm to evaluate the contribution of intracellular signaling cascades to the expression of ischemic tolerance. In this system, primary cultures are exposed to subtoxic chemical ischemia which provides subsequent protection against excitotoxicity. The goals of this research program are: 1) to identify the kinase pathways activated by cell stress which contribute to ischemic preconditioning, 2) to elucidate the mechanisms by which blockade of ROS results in alteration in potentially protective cellular chaperones and 3) to clarify the role of protein degradation and determine which, if any, binding partners limit and/or alter the transcription and neuroprotective activity of HSP 70. These studies will provide novel insight into endogenous molecular events that can be exploited to enhance neuronal survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050396-05
Application #
7536016
Study Section
Special Emphasis Panel (ZRG1-BDCN-D (01))
Program Officer
Hicks, Ramona R
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$331,093
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Lizama, Britney N; Palubinsky, Amy M; Raveendran, Vineeth A et al. (2018) Neuronal Preconditioning Requires the Mitophagic Activity of C-terminus of HSC70-Interacting Protein. J Neurosci :
Lizama, Britney N; Palubinsky, Amy M; McLaughlin, BethAnn (2018) Alterations in the E3 ligases Parkin and CHIP result in unique metabolic signaling defects and mitochondrial quality control issues. Neurochem Int 117:139-155
Palubinsky, Amy M; Stankowski, Jeannette N; Kale, Alixandra C et al. (2015) CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling. Antioxid Redox Signal 23:535-49
Grelli, Kimberly N; Palubinsky, Amy M; Kale, A Cozette et al. (2013) Alteration of isocitrate dehydrogenase following acute ischemic injury as a means to improve cellular energetic status in neuroadaptation. CNS Neurol Disord Drug Targets 12:849-60
Palubinsky, Amy M; Martin, Jacob A; McLaughlin, Bethann (2012) The role of central nervous system development in late-onset neurodegenerative disorders. Dev Neurosci 34:129-39
McLaughlin, Bethann; Buendia, Matthew A; Saborido, Tommy P et al. (2012) Haploinsufficiency of the E3 ubiquitin ligase C-terminus of heat shock cognate 70 interacting protein (CHIP) produces specific behavioral impairments. PLoS One 7:e36340
McKenzie, Jennifer R; Palubinsky, Amy M; Brown, Jacquelynn E et al. (2012) Metabolic multianalyte microphysiometry reveals extracellular acidosis is an essential mediator of neuronal preconditioning. ACS Chem Neurosci 3:510-8
Albers, Erin; Donahue, Brian S; Milne, Ginger et al. (2012) Perioperative plasma F(2)-Isoprostane levels correlate with markers of impaired ventilation in infants with single-ventricle physiology undergoing stage 2 surgical palliation on the cardiopulmonary bypass. Pediatr Cardiol 33:562-8
Klionsky, Daniel J (see original citation for additional authors) (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445-544
Zeiger, Stephanie L H; Stankowski, Jeannette N; McLaughlin, BethAnn (2011) Assessing neuronal bioenergetic status. Methods Mol Biol 758:215-35

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