Focal Brain Ischemia in the TNF Alpha Transgenic Rat

  • Pettigrew, Luther (PI)
  • KINDY, MARK (Former CoI)

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.
StatusFinished
Effective start/end date7/1/021/31/04

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.