Human brain ischemia and reperfusion (I/R) occurs clinically following stroke and cardiac arrest. Over 100 stroke and cardiac arrest clinical trials f neuroprotection have completely failed. This spectacular failure suggests there may be something fundamentally wrong with the current understanding of brain I/R. The current model of I/R injury, the "ischemic cascade", is a list of intracellular pathways induced in neurons by I/. We suggest that the failure of this viewpoint may rest in the assumption that a linear sequence of molecular changes causes outcome. We offer a novel, alternative, systems biology view of cell injury that posits all injury-induced changes in the cell contribute causally to outcome. Causality is not due to the action of linear pathways but to a nonlinear network of interactions. The theory is expressed by nonlinear ordinary differential equations. We seek to operationalize this theory by assessing means of measuring the differential equation variables. We propose the theory variables can be obtained from proteomic and transcriptomic data treated as quantitative deviations in the total amount of molecular damage and molecular stress responses from the control state. We propose to measure these distances in two classes of neurons, CA1 and CA3, using a well-studied model of global brain I/R in the rat.

Public Health Relevance

Human brain ischemia occurs during stroke or cardiac arrest, causing brain damage that leads to either life-long morbidity or death. The current dominant paradigm, the ischemic cascade has failed to provide successful clinical therapeutics for ischemic brain injury. Our nonlinear dynamical theory provides an alternative, systematic and mathematical approach to cell injury in general, and brain ischemia in particular, that may enhance the development of clinical therapeutics for stroke and cardiac arrest brain damage, thereby alleviating a major health care burden and cost.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS081347-02
Application #
8656456
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2013-05-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$188,100
Indirect Cost
$64,350
Name
Wayne State University
Department
Physiology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202