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Lay abstract (no permission to release technical abstract): Cholesterol is infamous due to its role in heart disease and consequently has become a main target in the fight against the disease. In Canada, there are 1.2 million people living with heart disease and over 81,000 people will die from it each year making it the leading cause of death for Canadians. Ironically, even though too much cholesterol is bad for our health, it cannot be completely removed from our bodies because it is essential for human life. Interestingly, while a key source of cholesterol is our diet, our cells can produce their own cholesterol, which is why controlling dietary cholesterol is not always enough to reduce cholesterol levels in the body. So, cholesterol-related heart disease is not only caused by eating too many hamburgers but is also due to the failure of our cells to regulate its "home-made" cholesterol. Until recently, cholesterol was thought to play only a structural role in human cells but now it is seen as an active player in many key cellular functions. Therefore, loss of cholesterol regulation in our bodies is not only causing physical blockages of arteries, resulting in heart disease, but it is also causing problems inside cells leading to disease states. In fact, recent studies have shown that the use of cholesterol reducing drugs decreased the incidence of breast cancer in Canadian women by 74% suggesting that proper cholesterol regulation is vital in the prevention of cancer. Thus, understanding how cholesterol is regulated inside the cell can lead to treatment avenues for two seemingly unlinked diseases, heart disease and cancer. There are three main aspects to the regulation of cholesterol in the cell: its production, its storage, and its location/transport. Recently, a group of cholesterol binding proteins have been identified and we have been able to show that they mediate many of the functions linked to cholesterol. Interestingly, when we remove these proteins from a cell, the regulation of cholesterol is lost and it accumulates inside cells. Also, these cells do not grow properly and eventually die. So, the goal of my project is to determine how these proteins affect cholesterol regulation and also to determine how these proteins mediate the cellular functions linked to cholesterol. These efforts will characterize a novel group of cholesterol regulators and identify new roles for cholesterol in the cell, which could lead to new drug treatment targets. It is difficult to study in humans a group of proteins that, when they are removed, cause death. To get around this issue, we use the baker's yeast as a model system since the regulation of cholesterol in yeast is similar to the regulation in humans. Baker's yeast is a very powerful tool because we can manipulate them in ways that are impossible in humans since there is no ethical problem if we mutate or kill a couple million yeast cells. The tools I will use to study the cholesterol binding proteins revolve around microscopy and genome manipulation. The cholesterol binding proteins in yeast and in humans are very similar in function, in turn studying these proteins in yeast will give great insight into the human proteins. Studying the yeast protein first is essential just as understanding the mechanics of a Ford car is essential before trying to understand a Ferrari. To characterize the function of cholesterol binding proteins on cholesterol regulation I will use microscopy to look for changes in the yeast after I remove/modify these proteins. By microscopy, I can see if the changes affect where cholesterol is in the cell and also identify other proteins that the changes affect. Furthermore, physical changes in the cell can tell me what cellular functions are affected, much like a bruise suggests that blood vessels are broken. After determining the cellular processes affected, I will use genome manipulation to find other genes that are involved in cholesterol regulation. These approaches will characterize new roles for cholesterol and determine how it mediates these functions through its binding proteins. A leading cause of heart disease is the loss of cholesterol regulation in the body and within cells. My research will show that key cholesterol regulators in the cell are cholesterol binding proteins and that these proteins mediate cholesterol's activities. Previously cholesterol was thought to be inert in the cell but my research will show that it is absolutely essential for various cellular processes. Only by truely understanding the role cholesterol plays in the cell will we be able to identify new drug targets that will have less side effects relative to the current broad spectrum cholesterol inhibitors. Furthermore, characterizing cholesterol dependent cellular functions will identify which processes could be mutated in cholesterol linked cancers. Thus, my research will lead to new and better treatment and preventative drug targets to improve the life of those suffering or at risk of heart disease and other cholesterol related diseases.

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