Grant: Discovery Grants Program - Individual

Vitamin E (known to most as a-tocopherol) is a fat-soluble vitamin that can protect the fats in our body (also known as lipids) from oxidizing and going rancid. Such damage occurs at a background rate even in healthy cells - part of the price of living in an oxygen-containing environment - but can increase during times of oxidative stress such as inflammation, autoimmune diseases, and exposure to pollution. Tissues have different demands for vitamin E. This raises a question: How does the body know to send dietary tocopherol to tissues where it is needed? We have made molecules that look like the natural vitamin, but that fluoresce when light is shone on them. This has allowed us to visualize how a fat-soluble vitamin moves around a water-filled cell. We now wish to make forms of vitamin E that would let us know exactly where in a lipid membrane it likes to spend its time. This is important for understanding how vitamin E works. Furthermore, some forms of vitamin E are metabolized very quickly and excreted. Some of these forms, however, have unique biological properties that might protect against the neuronal damage caused by strokes. We will prepare inhibitors of this metabolism that could enable the use of these rarer forms of vitamin E to protect neurons. Vitamin E is not soluble in the water inside of cells, and so needs specific carriers to ferry the molecule around. A protein in mammalian liver called the tocopherol transfer protein (TTP) accomplishes just this. We have shown how TTP can pick up tocopherol and carry it to a cell membrane, a structure composed of a number of different lipids. TTP likes to stick to some lipids and not others, indeed it even likes lipids that cause membranes to be curved rather than flat. We now wish to use our expertise with TTP to enquire of other proteins that also move lipids around cells. The two families that we will focus on are responsible for transporting molecules like cholesterol and the very lipids that make up membranes. We know that cells have many ways of controlling how these proteins work, but no one has measured how well the proteins can stick to membranes, nor whether they like to stick to certain membrane over others.