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329 Heritage Medical
Research Centre
University of Alberta
Edmonton, Alberta
T6G 2S2 Canada
Jean Vance, PhD
Professor of Medicine, FRSC

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The research in my laboratory is focused on the regulation of lipid synthesis and intracellular trafficking in mammalian cells.

Regulation of phosphatidylserine synthesis. In mammalian cells phosphatidylserine (PS) is synthesized on the endoplasmic reticulum and mitochondria-associated membranes by two different PS synthases, PSS1 and PSS2. PS is an important membrane phospholipid that is required for the blood-clotting cascade, for recognition and removal of apoptotic cells, and for activation of specific enzymes such as protein kinase C. PS is also key precursor of phosphatidylethanolamine. PSS1 and PSS2 catalyze parallel reactions but are encoded by different genes. To test our hypothesis that each PSS isoform performs a specific function we have generated genetically-modified mice in which the gene encoding either PSS1 or PSS2 has been disrupted. We obtained viable PSS2-deficient mice and have shown that the male knock-out mice are subfertile. We have recently generated PSS1-deficient mice that are viable and we are currently characterizing these mice. Furthermore, we have found that disruption of the PS decarbxoylase gene in mice is embryonic lethal and results in mitochondrial abnormalities, likely a defet in mitochondrial fusion, presumably because of a deficiency of mitochondrial phosphatidylethanolamine. In addition, we are studying the transcriptional regulation of the PSS1, PSS2 and PS decarboxylase genes.

Lipid synthesis and transport in neurons. Increasing evidence is linking defects in cholesterol metabolism in the brain to neurodegenerative disorders such as Alzheimer's disease, Smith-Lemmli-Opitz disease and Niemann-Pick C disease. Neurons are polarized cells in which the cell body is often located a great distance from the distal axon. Consequently, these cells provide a unique model for studying intracellular lipid trafficking. We culture primary sympathetic neurons and retinal ganglion cells (CNS neurons) from rats and mice in compartmented culture dishes in which the cell body is located in one compartment and distal axons extend into adjacent compartments that contain separate fluid environments. We have shown that the synthesis of phospholipids and cholesterol is important for normal axonal growth. Moroever, although phospholipid synthesis occurs in cell bodies and axons, cholesterol synthesis is restricted to cell bodies. We study neurons from the mouse model for Niemann-Pick C (NPC) disease which is a severe, progressive neurological disorder caused by a defect in intracellular cholesterol trafficking. We have shown that although NPC1-deficient cell bodies accumulate cholesterol abnormally, the cholesterol content of axons is reduced and cholesterol trafficking to axons is impaired. Our recent data suggest that NPC1 in distal axons participates in synaptic vesicle recycling. We are also examining whether or not activated microglia in the brains of NPC1-deficient mice enhance neuronal death in this disease. Another project that is on-going in the lab is to determine the mechanisms by which apo E-containing lipoproteins secreted by astrocytes enhance axon growth and strikingly protect neurons from apoptosis. Our data indicate that these lipoproteins initiate a signalling pathway that promotes neuron survival.

 
Last Updated on Thursday, 07 January 2010 16:46