Cytoprotective effects of intracellular platelet activating factor acetylhydrolases

Abstract

Platelet activating factor (PAF) is a biologically active phospholipid implicated in the developmental brain disorder Miller-Dieker Syndrome (MDS) and purported to be a primary mediator of cell death in HIV-dementia, ischemia, and epilepsy. As part of my honour's thesis, I demonstrated that PAF can elicit cell death independently of its G-protein coupled receptor (PAFR) in PC12 cells. In my M.Sc. research, I have sought to identify how PAF-mediated cell death is regulated in PC12 cells. PAF is inactivated in brain by two intracellular PAF-acetylhydrolases (PAF-AHs): PAF-AH I and PAF-AH II. PAF-AH I is a trimeric complex composed of two catalytic subunits (alpha1 and alpha2) and one regulatory subunit (beta). Mutations in the Lis1 gene, coding for the beta subunit of PAF-AH I, are the genetic determinant of MDS. However, it is not clear whether these mutations impact on PAF-AH I enzymatic activity in MDS. Furthermore, it is not known whether cytosolic PAF-AH activity regulates the kinetics of neuronal loss following pathophysiological challenge. To begin to address these questions, I sought to identify an in vitro model system suitable for study of PAF-AH activity.* (Abstract shortened by UMI.) *This dissertation is a compound document (contains both a paper copy and a CD as part of the dissertation). The CD requires the following system requirements: QuickTime.