Stroke is a devastating and debilitating condition resulting from a blockage or
hemorrhage in the vasculature of the brain. Despite extensive research, the etiology
and pathophysiology of the disease at the level of the cell membrane are poorly
understood, and effective treatment has been elusive. Though much research has
shown marked increases in lipid metabolism following stroke, the impact of these
changes have often been overlooked given the technical challenges associated with
identifying regionally specific changes in degenerating tissue. The advent of
lipidomics – a systems biology approach to the large-scale profiling of individual
lipid species in tissues – has renewed interest in understanding the role of
membrane lipids and their metabolites in the cell and in ischemic injury. In this
thesis, I have used an unbiased LC-ESI-MS-based lipidomic approach to profile the
small molecular weight glycerophosphocholine second messenger lipidome in
anterior and posterior regions of cortex and striatum in the forebrain of wild-type and
platelet activating factor receptor (PAFR) null-mutant mice before and after middle
cerebral artery occlusion (MCAO). From these profiles, I have outlined the potential
use of lipid second messenger distribution as topographic landmarks to identify
functional subdomains within neural tissue. Further, I have demonstrated that
ischemia does not simply disrupt lipid second messenger metabolism globally but
produces regionally specific changes in discrete species and that these changes are
altered by the loss of lipid regulatory effectors (i.e., PAFR null mutation). Based on
the lipid species identified in this profile of healthy and ischemic tissue, I proposed
that tight regulation of PC(O-22:6/2:0) homeostasis by PAFR-expressing microglia is
ii
required for proper dopaminergic signaling in prefrontal cortex. Finally, I have
outlined a model whereby increased PAF synthesis following ischemia contributes
the inflammatory response by promoting blood-brain barrier permeability, microglial
activation and immune cell infiltration in a PAFR-dependent manner.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OOU.#10393/20536 |
| Date | 11 January 2012 |
| Creators | Syrett, Andrew J. |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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