Project 4:
Lipid-Mediated Signaling and Neuroinflammation
Investigator: Dr. Thad Rosenberger

The objectives of this proposal are to determine the contribution that phospholipases A₂ (PLA₂)- and phospholipases C (PLC)-mediated signal transduction have in the progression of cell loss in a rat model on neuroinflammation. These studies are relevant because neuroinflammation is an important factor in the pathogenesis of a number of human neurodegenerative disorders. Activation of these phospholipases participates in the neuroinflammatory cascade by releasing second messenger molecules that influence ionic channels and glutamate release, and that can be converted to biologically active eicosanoids. Induction of these cascades disrupts brain metabolism and increases the expression of enzymes found in the inflammatory cascades. However, little is known concerning the contribution that these signaling pathways have in the sequel of events that result in cell death during neuroinflammation. We have found, using a rat model of neuroinflammation, that the turnover of brain arachidonic acid and the activity of types IVA cytosolic phospholipases A₂ (cPLA₂) and IIA secretory phospholipases A₂ (sPLA₂) are significantly increased well before the onset of cholinergic cell death and memory dysfunction, both are characteristics of this model. These data suggest that phospholipase activation precedes neuroinflammation-induced injury and possibly offers a therapeutic point of intervention. Our central hypothesis is that phospholipase activation is an initial convergence point of the neuroinflammatory reaction and is essential for the progression of injury that results in cell death. The significance of this proposal is that applying in vivo and in vitro-based techniques will allow us to determine specifically the contribution that these lipid-mediated signaling pathways have in the progression of degenerative events associated with neuroinflammation. These techniques can also be used to determine the contribution that lipid-mediated signaling has in other animal models in which enzymes and receptors have been altered or knocked out.