Tumor necrosis factor-alpha (TNFalpha) is a pleotrophic cytokine secreted by astroglia, macrophages, and other cells participating in the inflammatory reaction initiated by cerebral infarction. Levels of TNFalpha rise sequentially in the infarct core, the ischemic penumbra, and in unaffected tissue in human brain damaged by stroke and may persist up to 40 days afterward. The Overall Goal of this R01 proposal is to establish the TNFalpha-transgenic rat as a new model for investigation of TNF receptor (TNFR)-mediated signal transduction and cell death pathways activated during brain infarction in man. This animal was constructed to overexpress the murine TNFalpha gene with its own promoter and has never been used to investigate the pathophysiology of any brain disorder. Cerebral tissue obtained from the transgenic rat shows elevated levels of TNFalpha mRNA and protein. When subjected to middle cerebral artery occlusion, transgenic animals have larger mean percent infarct volume than wild type controls. We will employ this unique animal to test our principal Hypothesis: Upregulated synthesis of TNFalpha in ischemic brain augments neuronal apoptosis by receptor-mediated activation of signal transduction cascades. We propose to accomplish the following Specific Aims: 1) to characterize the neurochemical and cerebrovascular anatomy, physiology, and cognitive function of the TNFalpha-transgenic rat under normal conditions and in response to ischemic brain injury, 2) to identify the cellular origin of TNFalpha and define the immune response to cerebral ischemic injury in the TNFalpha-transgenic rat, 3) to use the transgenic animal to simulate how elevated TNFalpha levels affect TNFR number or distribution and modulate signal transduction cascades in ischemic human brain, 4) to use the transgenic animal to simulate how elevated TNFalpha levels influence apoptotic neuronal degeneration in ischemic human brain, and 5) to assess the research utility of the TNFalpha-transgenic rat as a model for therapeutic intervention by determining if pre- or post-ischemic inhibition of TNFalpha synthesis attenuates ischemic injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047395-02
Application #
6846319
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Jacobs, Tom P
Project Start
2004-02-01
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$272,505
Indirect Cost
Name
University of Kentucky
Department
Neurology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Pettigrew, L Creed; Kryscio, Richard J; Norris, Christopher M (2016) The TNF?-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss. PLoS One 11:e0154721
Pettigrew, L Creed; Kindy, Mark S; Scheff, Stephen et al. (2008) Focal cerebral ischemia in the TNFalpha-transgenic rat. J Neuroinflammation 5:47
Korde, Amit S; Pettigrew, L Creed; Craddock, Susan D et al. (2007) Protective effects of NIM811 in transient focal cerebral ischemia suggest involvement of the mitochondrial permeability transition. J Neurotrauma 24:895-908
Korde, Amit S; Pettigrew, L Creed; Craddock, Susan D et al. (2005) The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia. J Neurochem 94:1676-84