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
Structure-function And Domain Minimization Of Insulin-like Peptide 3, A Novel Member Of The Insulin Superfamily.
Funder
National Health and Medical Research Council
Funding Amount
$288,000.00
Summary
Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selectio ....Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selection. More recent evidence shows that the peptide has clear roles in modulating male and female germ cell maturation. These effects indicate that agonists and antagonists of INSL3 have potential as specific drugs for novel contraceptive approaches or infertility treatments in both sexes. The actions of INSL3 are mediated by interaction with a G-protein coupled receptor known as LGR8. This receptor is expressed in the testes and ovary as well as several other tissues including the brain. However, very little is known about how INSL3 interacts with LGR8 to produce its physiological responses. Consequently, we will determine the structural features of the peptide that are responsible for receptor binding. This will be achieved by use of chemical peptide synthesis of not only INSL3 but also of analogues of the peptide that contain modified residues or domains. These will be assayed for characteristic INSL3 activity and the results, together with those acquired by modern biomolecular interaction analyses, will be used to identify the receptor binding regions for INSL3. This information, together with a determination of the three-dimensional structure of INSL3 by using NMR spectroscopy, will then be disseminated using computer-assisted molecular modelling to design smaller, more stable, orally active analogues. Such mimetics of reduced size that are correspondingly cheaper and simpler to prepare and handle will have great potential for therapeutic regulators of human fertility.Read moreRead less