Grants and Contracts Details
Description
The overall goal of this Grant-in-Aid proposal is to characterize and validate an in vivo model of focal cerebral
ischemia in a novel transgenic rat strain overexpressing the murine tumor necrosis factor-alpha (TNF-alpha)
gene. Tumor necrosis factor belongs to a superfamily of cytokines that may enhanCE!or deter neuronal survival
by activation of intracellular signaling cascades. Soluble TNF-alpha is derived through proteolytic cleavage
from its membrane-bound precursor by TNF-alpha-convertase (TACE). Among neural cell lines, TNF-alpha is
secreted robustly by microglia andastrocytes. Neurons possess the p55 and p75 subtypes of TNF receptors
(TNFRs). When activated, TNFRs promote the synthesis of the nuclear transcription factor, NFkappaB, and
link to signal transduction pathways featuring mitogen-activated protein kinase (MAPK) and the
stress-activated protein and JUN kinase (SAPKlJNK) molecule. Through associated release of NFkappaB, the
two derivative paths enhance the transcription of genes that may promote neuronal survival or death. From our
preliminary studies, we anticipate that TNF-mediated signal transduction in the brain of our transgenic animal
stimulates neuronal death and magnifies ischemic injury. We will employ this novel transgenic rat strain to test
our hypothesis stating that genetic overexpression of TNF-alpha will augment neuronal degeneration and glial
activation in focal cerebral ischemia. All animals will undergo suture occlusion of the middle cerebral artery.
We will accomplish the following specific aims: 1) To determine if overexpression of the TNF-alpha gene alters
the spatiotemporal distribution of stressed or apoptotic neurons, TNFRs, or activated glia in the maturing
infarct and 2) To determine if overexpression of the TNF-alpha gene modulates TACE or is associated with
selective activation of the SAPKlJNK or MAPK pathways in neurons threatened by ischemic stress.
Status | Finished |
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Effective start/end date | 7/1/02 → 1/31/04 |
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