Grant: Discovery Grants Program - Individual

Why is Vitamin E an  essential vitamin?   Vitamin E  is a strong antioxidant preservative in our food and personal care products. Vitamin E deficiencies are rare, however, healthy concentrations in our bodies are so low that some researchers are looking for reasons for consuming vitamin E other than  oxidation protection. Worse still, there are no known health benefits for supplementing with vitamin E, and not for lack of trying.  Thus the purpose for vitamin E is still hotly debated, over 90 years since its discovery. We are filling in several knowledge gaps of how tocopherol molecules (ie. vitamin E) interacts with the cell membrane. Our research goal is to convince physiologists that the demise of the antioxidant theory of tocopherol is premature. We view tocopherol as a counterpoint to cholesterol in how lipid soluble molecules work among the lipids of the cell membrane. In brief; the molecular structure of tocopherol is just right to locate itself among the right lipids at the right place for oxidation protection.  We have already seen that tocopherol location is not universal and suggested a means of free radical termination. This research proposal is designed to answer key questions:  Does tocopherol target oxidation-sensitive lipids ? Tocopherol should associate with the lipids that require oxidation protection. We will measure the association constants of the vitamin with lipids of varying degrees of unsaturation. Neutron and X-ray diffraction is our primary tool for structural determination, used to measure nanoscopic domains formed with tocopherol, as well as any asymmetric distribution in membranes.  Does the disorder of unsaturated lipids help tocopherol? We can use monolayers to control the lipid chain order through surface pressure, and monitor how tocopherol slows oxidation damage. In an oxygen-free environment we control the rate of radical generation, and note the rate of lipid degradation. This deceptively simple experiment decouples the effects of stopping reactive oxygen species and termination of alkyl peroxyl radicals.  Just what is the rate of tocopherol diffusion? Literature values of tocopherol's diffusion vary by orders of magnitude, due to poor controls and wrong test lipids. Using NMR, we will measure the diffusion rate of tocopherol to reveal any lipid preference.  What is the effect of lipids on tocopherol's structure? Tocopherol has a chiral centre which can report on its molecular structure, and we have found a solvent polarity dependence. With synchrotron bright UV light, we will look for the effect of different lipids on its atomic structure. Are there lessons from tocopherol analogues?  I am currently engaged in a commercial project exploring tocopherol-like molecules for cancer detection, but how they work is a general interest research topic. These new molecules differ from natural tocopherol in subtle ways and the above experiments will help us understand tocopherol better.