Novel Omega-3 Fatty Acid Epoxides And The Activation Of Cellular Survival Pathways
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Recent studies have reported that foods and oils containing high levels of omega-3 fatty acids have beneficial effects in patients with arthritis and cardiovascular disease. The mechanisms by which these dietary changes produce health benefits are unclear but it is known that omega-3 fatty acids can replace omega-6 and other fatty acids in cells; these omega-6 acids are more common in western diets. A number of enzymes in cells convert fatty acids to oxygenated derivatives and some of these have ....Recent studies have reported that foods and oils containing high levels of omega-3 fatty acids have beneficial effects in patients with arthritis and cardiovascular disease. The mechanisms by which these dietary changes produce health benefits are unclear but it is known that omega-3 fatty acids can replace omega-6 and other fatty acids in cells; these omega-6 acids are more common in western diets. A number of enzymes in cells convert fatty acids to oxygenated derivatives and some of these have potent protective effects that allow cells to survive in the presence of toxic stimuli. We have found that epoxides formed from the omega-3 fatty acid stearidonic acid are extremely potent protective agents in cells - more so that epoxides from omega-6 acids like arachidonic acid. The present project seeks to identify omega-3 fatty acid epoxides with potent and long-lived beneficial effects in cells, relate these properties to those of omega-6 fatty acid epoxides and then understand how the omega-3 epoxides enhance cell survival. The findings will provide a rational basis from which to understand the beneficial effects of dietary modification already seen in clinical studies. By understanding the biochemical and molecular events in cells that are activated by omega-3 fatty acid epoxides we may be able to design therapies, most likely involving changes in dietary fat intake, that could benefit individuals with arthritic, cardiovascular and other conditions. Given the high incidence of these conditions in this country the potential impact of the findings from this project could be highly significant and are consistent with the national research priority healthy ageing.Read moreRead less
Functional Interplay Of Transcriptional Activators In The Regulation Of The Cytoprotective Human CYP2J2 Gene
Funder
National Health and Medical Research Council
Funding Amount
$480,828.00
Summary
Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have ....Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have been able to do this but we now know that the biologically important vitamin A derivative all-trans-retinoic acid (ATRA) can increase CYP2J2 in cells. In this project we will build on this novel finding to develop treatments that increase CYP2J2 in tissues. About 10% of people have a variant CYP2J2 gene that differs from the common form by one nucleotide. This polymorphic variant can decrease the amount of the CYP2J2 enzyme and increase cardiovascular risk. We ve found that this polymorphism is located in a critical control region of the gene and affects how the gene responds to transcription factors. The present project will study in detail the regulation of the CYP2J2 gene and its naturally occurring variant by transcription factors that bind to this control region. We will also test how the polymorphic version of the gene responds to stress stimuli and to treatments like ATRA that increase the amount of the wild-type gene in cells. Studying human gene regulation is difficult because we cannot easily measure their levels in individuals. So we will make transgenic mice to study human CYP2J2 regulation and will test whether the treatments we devise in cells also work in vivo. These studies will help us to design pharmacological strategies to increase CYP2J2 in cells. By maintaining the beneficial effects of CYP2J2, and understanding how these are altered in the variant, a significant outcome of the project could be a new treatment of cardiovascular disease.Read moreRead less